# THE CONCISE GUIDE TO PHARMACOLOGY
## 2019/20: G protein-coupled receptors

Stephen Alexander, Arthur Christopoulos, Anthony P Davenport, Eamonn Kelly, Alistair Mathie, John Peters, Emma Veale, Jane Armstrong, Elena Faccenda, Simon Harding, et al.

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► To cite this version:

Stephen Alexander, Arthur Christopoulos, Anthony P Davenport, Eamonn Kelly, Alistair Mathie, et al.. THE CONCISE GUIDE TO PHARMACOLOGY 2019/20: G protein-coupled receptors. British Journal of Pharmacology, 2019, 176 (S1), pp.S21-S141. 10.1111/bph.14748. hal-02388696

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# THE CONCISE GUIDE TO PHARMACOLOGY 2019/20: G protein-coupled receptors

Stephen PH Alexander<fnref n="1" /> ID, Arthur Christopoulos<fnref n="2" /> ID, Anthony P Davenport<fnref n="3" /> ID, Eamonn Kelly<fnref n="4" />, Alistair Mathie<fnref n="5" /> ID, John A Peters<fnref n="6" /> ID, Emma L Veale<fnref n="5" /> ID, Jane F Armstrong<fnref n="7" /> ID, Elena Faccenda<fnref n="7" /> ID, Simon D Harding<fnref n="7" /> ID, Adam J Pawson<fnref n="7" /> ID, Joanna L Sharman<fnref n="7" /> ID, Christopher Southan<fnref n="7" /> ID, Jamie A Davies<fnref n="7" /> ID and CGTP Collaborators

<figure><img src="image_3.png" /></figure>

## Abstract

The Concise Guide to PHARMACOLOGY 2019/20 is the fourth in this series of biennial publications. The Concise Guide provides concise overviews of the key properties of nearly 1800 human drug targets with an emphasis on selective pharmacology (where available), plus links to the open access knowledgebase source of drug targets and their ligands (www guidetopharmacology.org), which provides more detailed views of target and ligand properties. Although the Concise Guide represents approximately 400 pages, the material presented is substantially reduced compared to information and links presented on the website. It provides a permanent, citable, point-in-time record that will survive database updates. The full contents of this section can be found at http://onlinelibrary.wiley.com/doi/10.1111/bph.14748. G protein-coupled receptors are one of the six major pharmacological targets into which the Guide is divided, with the others being: ion channels, nuclear hormone receptors, catalytic receptors, enzymes and transporters. These are presented with nomenclature guidance and summary information on the best available pharmacological tools, alongside key references and suggestions for further reading. The landscape format of the Concise Guide is designed to facilitate comparison of related targets from material contemporary to mid-2019, and supersedes data presented in the 2017/18, 2015/16 and 2013/14 Concise Guides and previous Guides to Receptors and Channels. It is produced in close conjunction with the International Union of Basic and Clinical Pharmacology Committee on Receptor Nomenclature and Drug Classification (NC-IUPHAR), therefore, providing official IUPHAR classification and nomenclature for human drug targets, where appropriate.

## Conflict of interest

The authors state that there are no conflicts of interest to disclose.

© 2019 The Authors. British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of The British Pharmacological Society.

This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

**Overview:** G protein-coupled receptors (GPCRs) are the largest class of membrane proteins in the human genome. The term "7TM receptor" is commonly used interchangeably with "GPCR", although there are some receptors with seven transmembrane domains that do not signal through G proteins. GPCRs share a common architecture, each consisting of a single polypeptide with an extracellular N-terminus, an intracellular C-terminus and seven hydrophobic transmembrane domains (TM1-TM7) linked by three extracellular loops (ECL1-ECL3) and three intracellular loops (ICL1-ICL3). About 800 GPCRs have been identified in man, of which about half have sensory functions, mediating olfaction (~400), taste (33), light perception (10) and pheromone signalling (5) [1479]. The remaining 350 non-sensory GPCRs mediate signalling by ligands that range in size from small molecules to peptides to large proteins; they are the targets for the majority of drugs in clinical usage [1642, 1772], although only a minority of these receptors are exploited therapeutically. The first classification scheme to be proposed for GPCRs [1129] divided them, on the basis of sequence homology, into six classes. These

<footnote n="1">¹School of Life Sciences, University of Nottingham Medical School, Nottingham, NG7 2UH, UK</footnote>

<footnote n="2">²Monash Institute of Pharmaceutical Sciences and Department of Pharmacology, Monash University, Parkville, Victoria 3052, Australia</footnote>

<footnote n="3">³Clinical Pharmacology Unit, University of Cambridge, Cambridge, CB2 0QQ, UK</footnote>

<footnote n="4">⁴School of Physiology, Pharmacology and Neuroscience, University of Bristol, Bristol, BS8 1TD, UK</footnote>

<footnote n="5">⁵Medway School of Pharmacy, The Universities of Greenwich and Kent at Medway, Anson Building, Central Avenue, Chatham Maritime, Chatham, Kent, ME4 4TB, UK</footnote>

<footnote n="6">⁶Neuroscience Division, Medical Education Institute, Ninewells Hospital and Medical School, University of Dundee, Dundee, DD1 9SY, UK</footnote>

<footnote n="7">⁷Centre for Discovery Brain Sciences, University of Edinburgh, Edinburgh, EH8 9XD, UK</footnote>
classes and their prototype members were as follows: **Class A** (rhodopsin-like), **Class B** (secretin receptor family), **Class C** (metabotropic glutamate), **Class D** (fungal mating pheromone receptors), **Class E** (cyclic AMP receptors) and **Class F** (frizzled/smoothened). Of these, classes D and E are not found in vertebrates. An alternative classification scheme "GRAFS" [1890] divides vertebrate GPCRs into five classes, overlapping with the A-F nomenclature, viz:

**Glutamate family (class C)**, which includes metabotropic glutamate receptors, a calcium-sensing receptor and GABA<sub>B</sub> receptors, as well as three taste type 1 receptors and a family of pheromone receptors (V2 receptors) that are abundant in rodents but absent in man [1479].

**Rhodopsin family (class A)**, which includes receptors for a wide variety of small molecules, neurotransmitters, peptides and hormones, together with olfactory receptors, visual pigments, taste type 2 receptors and five pheromone receptors (V1 receptors).

**Adhesion family** GPCRs are phylogenetically related to class B receptors, from which they differ by possessing large extracellular N-termini that are autoproteolytically cleaved from their 7TM domains at a conserved "GPCR proteolysis site" (GPS) which lies within a much larger (320 residue) "GPCR autoproteolysis-inducing" (GAIN) domain, an evolutionary ancient motif also found in polycystic kidney disease 1 (PKD1)-like proteins, which has been suggested to be both required and sufficient for autoproteolysis [1743].

**Frizzled family** consists of 15 Frizzled proteins (FZD(1-10)) and Smoothened (SMO). The FZDs are activated by secreted lipoglycoproteins of the WNT family, whereas SMO is indirectly activated by the Hedgehog (HH) family of proteins acting on the transmembrane protein Patched (PTCH).

**Secretin family**, encoded by 15 genes in humans. The ligands for receptors in this family are polypeptide hormones of 27-141 amino acid residues; nine of the mammalian receptors respond to ligands that are structurally related to one another (glucagon, glucagon-like peptides (GLP-1, GLP-2), glucose-dependent insulinotropic polypeptide (GIP), secretin, vasoactive intestinal peptide (VIP), pituitary adenylate cyclase-activating polypeptide (PACAP) and growth-hormone-releasing hormone (GHRH)) [811].

## GPCR families

<table><thead><tr><th>Family</th><th>Class A</th><th>Class B (Secretin)</th><th>Class C (Glutamate)</th><th>Adhesion</th><th>Frizzled</th></tr></thead><tbody><tr><td>Receptors with known ligands</td><td>197</td><td>15</td><td>12</td><td>0</td><td>11</td></tr><tr><td>Orphans</td><td>87 (54)<sup>a</sup></td><td>-</td><td>8 (1)<sup>a</sup></td><td>26 (6)<sup>a</sup></td><td>0</td></tr><tr><td>Sensory (olfaction)</td><td>390<sup>b,c</sup></td><td>-</td><td>-</td><td>-</td><td>-</td></tr><tr><td>Sensory (vision)</td><td>10<sup>d</sup> opsins</td><td>-</td><td>-</td><td>-</td><td>-</td></tr><tr><td>Sensory (taste)</td><td>30<sup>c</sup> taste 2</td><td>-</td><td>3<sup>c</sup> taste 1</td><td>-</td><td>-</td></tr><tr><td>Sensory (pheromone)</td><td>5<sup>c</sup> vomeronasal 1</td><td>-</td><td>-</td><td>-</td><td>-</td></tr><tr><td>Total</td><td>719</td><td>15</td><td>22</td><td>33</td><td>11</td></tr></tbody></table>

Much of our current understanding of the structure and function of GPCRs is the result of pioneering work on the visual pigment rhodopsin and on the β<sub>2</sub> adrenoceptor, the latter culminating in the award of the 2012 Nobel Prize in chemistry to Robert Lefkowitz and Brian Kobilka [1121, 1244].

## Pseudogenes

Below is a curated list of pseudogenes that in humans are non-coding for receptor protein. In some cases these have a shared ancestry with genes that encode functional receptors in rats and mice.

ADGRE4P, GNRHR2, GPR79, HTR5BP, NPY6R, TAAR3P, TAAR4P, TAAR7P, TAS2R12P, TAS2R15P, TAS2R18P, TAS2R2P, TAS2R62P, TAS2R63P, TAS2R64P, TAS2R67P, TAS2R68P, TAS2R6P. A more detailed listing containg further information can be viewed here.

## Olfactory receptors

Olfactory receptors are also seven-transmembrane spanning G protein-coupled receptors, responsible for the detection of odorants. These are not currently included as they are not yet associated with extensive pharmacological data but are curated in the following databases: The gene list of olfactory receptors at HGNC, and curated by HORDE and ORDB.

<footnote><sup>a</sup>Numbers in brackets refer to orphan receptors for which an endogenous ligand has been proposed in at least one publication, see [455]; <sup>b</sup>[1634]; <sup>c</sup>[1479]; <sup>d</sup>[2109].</footnote>
## Further reading on G protein-coupled receptors

Kenakin T. (2018) Is the Quest for Signaling Bias Worth the Effort? *Mol. Pharmacol.* **93**: 266-269 [PMID:29348268]

Michel MC et al. (2018) Biased Agonism in Drug Discovery-Is It Too Soon to Choose a Path? *Mol. Pharmacol.* **93**: 259-265 [PMID:29326242]

## Family structure

S23 Orphan and other 7TM receptors

S24 Class A Orphans

- Class B Orphans

S33 Class C Orphans

- Opsin receptors

S33 Taste 1 receptors

S34 Taste 2 receptors

S35 Other 7TM proteins

S36 5-Hydroxytryptamine receptors

S39 Acetylcholine receptors (muscarinic)

S41 Adenosine receptors

S42 Adhesion Class GPCRs

S45 Adrenoceptors

S48 Angiotensin receptors

S50 Apelin receptor

S51 Bile acid receptor

S51 Bombesin receptors

S53 Bradykinin receptors

S54 Calcitonin receptors

S56 Calcium-sensing receptor

S57 Cannabinoid receptors

S58 Chemerin receptors

S59 Chemokine receptors

S63 Cholecystokinin receptors

S64 Class Frizzled GPCRs

S67 Complement peptide receptors

S68 Corticotropin-releasing factor receptors

S69 Dopamine receptors

S71 Endothelin receptors

S72 G protein-coupled estrogen receptor

S73 Formylpeptide receptors

S74 Free fatty acid receptors

S76 GABAB receptors

S78 Galanin receptors

S79 Ghrelin receptor

S80 Glucagon receptor family

S81 Glycoprotein hormone receptors

S82 Gonadotrophin-releasing hormone receptors

S83 GPR18, GPR55 and GPR119

S84 Histamine receptors

S86 Hydroxycarboxylic acid receptors

S87 Kisspeptin receptor

S88 Leukotriene receptors

S89 Lysophospholipid (LPA) receptors

S90 Lysophospholipid (S1P) receptors

S92 Melanin-concentrating hormone receptors

S93 Melanocortin receptors

S94 Melatonin receptors

S95 Metabotropic glutamate receptors

S97 Motilin receptor

S98 Neuromedin U receptors

S99 Neuropeptide FF/neuropeptide AF receptors

Roth BL et al. (2017) Discovery of new GPCR ligands to illuminate new biology. *Nat. Chem. Biol.* **13**: 1143-1151 [PMID:29045379]

Sriram K et al. (2018) G Protein-Coupled Receptors as Targets for Approved Drugs: How Many Targets and How Many Drugs? *Mol. Pharmacol.* **93**: 251-258 [PMID:29298813]

# Orphan and other 7TM receptors

G protein-coupled receptors → Orphan and other 7TM receptors

**Overview:** This set contains 'orphan' G protein coupled receptors where the endogenous ligand(s) is not known, and other 7TM receptors.

S100 Neuropeptide S receptor

S101 Neuropeptide W/neuropeptide B receptors

S102 Neuropeptide Y receptors

S103 Neurotensin receptors

S104 Opioid receptors

S106 Orexin receptors

S107 Oxoglutarate receptor

S108 P2Y receptors

S110 Parathyroid hormone receptors

S111 Platelet-activating factor receptor

S112 Prokineticin receptors

S113 Prolactin-releasing peptide receptor

S114 Prostanoid receptors

S116 Proteinase-activated receptors

S117 QRFP receptor

S118 Relaxin family peptide receptors

S120 Somatostatin receptors

S121 Succinate receptor

S122 Tachykinin receptors

S123 Thyrotropin-releasing hormone receptors

S124 Trace amine receptor

S125 Urotensin receptor

S126 Vasopressin and oxytocin receptors

S127 VIP and PACAP receptors
# Class A Orphans

G protein-coupled receptors → Orphan and other 7TM receptors → Class A Orphans

**Overview:** Table 1 lists a number of putative GPCRs identified by **NC-IUPHAR [612]**, for which preliminary evidence for an endogenous ligand has been published, or for which there exists a potential link to a disease, or disorder. These GPCRs have recently been reviewed in detail [455]. The GPCRs in Table 1 are all Class A, rhodopsin-like GPCRs. Class A orphan GPCRs not listed in Table 1 are putative GPCRs with as-yet unidentified endogenous ligands.

<table><caption>**Table 1:** Class A orphan GPCRs with putative endogenous ligands</caption><tr><td>GPR3</td><td>GPR4</td><td>GPR6</td><td>GPR12</td><td>GPR15</td><td>GPR17</td><td>GPR20</td></tr><tr><td>GPR22</td><td>GPR26</td><td>GPR31</td><td>GPR34</td><td>GPR35</td><td>GPR37</td><td>GPR39</td></tr><tr><td>GPR50</td><td>GPR63</td><td>GRP65</td><td>GPR68</td><td>GPR75</td><td>GPR84</td><td>GPR87</td></tr><tr><td>GPR88</td><td>GPR132</td><td>GPR149</td><td>GPR161</td><td>GPR183</td><td>LGR4</td><td>LGR5</td></tr><tr><td>LGR6</td><td>MAS1</td><td>MRGPRD</td><td>MRGPRX1</td><td>MRGPRX2</td><td>P2RY10</td><td>TAAR2</td></tr></table>

In addition the orphan receptors *GPR18*, *GPR55* and *GPR119* which are reported to respond to endogenous agents analogous to the endogenous cannabinoid ligands have been grouped together (GPR18, GPR55 and GPR119).

Nomenclature GPR3

HGNC, UniProt GPR3, P46089

Agonists diphenyleneiodonium chloride [2388]

Endogenous ligands –

Comments Sphingosine 1-phosphate was reported to be an endogenous agonist [2168], but this finding was not replicated in subsequent studies [2389]. Reported to activate adenylyl cyclase constitutively through Gs [545]. Gene disruption results in premature ovarian ageing [1234], reduced β-amyloid deposition [2112] and hypersensitivity to thermal pain [1837] in mice. First small molecule inverse agonist [993] and agonists identified [2386]

GPR4

GPR4, P46093

–

Protons

An initial report suggesting activation by lysophosphatidylcholine and sphingosylphosphorylcholine [2440] has been retracted [1597]. GPR4, GPR65, GPR68 and GPR132 are now thought to function as proton-sensing receptors detecting acidic pH [455, 1932]. Gene disruption is associated with increased perinatal mortality and impaired vascular proliferation [2377]. Negative allosteric modulators of GPR4 have been reported [2137].

GPR6

GPR6, P46095

–

–

An initial report that sphingosine 1-phosphate (S1P) was a high-affinity ligand (EC50 value of 39nM) [941, 2168] was not repeated in arrestin-based assays [2015, 2389]. Reported to activate adenylyl cyclase constitutively through Gs and to be located intracellularly [1644]. GPR6-deficient mice showed reduced striatal cyclic AMP production *in vitro* and selected alterations in instrumental conditioning *in vivo*. [1309].
<table><tr><td>Nomenclature</td><td>GPR12</td><td>GPR15</td><td>GPR17</td></tr><tr><td>HGNC, UniProt</td><td>GPR12, P47775</td><td>GPR15, P49685</td><td>GPR17, Q13304</td></tr><tr><td>Endogenous agonists</td><td>–</td><td>–</td><td>UDP-glucose [143, 395], LTC<sub>4</sub> [395], UDP-galactose [143, 395], uridine diphosphate [143, 395], LTD<sub>4</sub> [395]</td></tr><tr><td>Comments</td><td>Reports that sphingosine 1-phosphate is a ligand of GPR12 [940, 2168] have not been replicated in arrestin-based assays [2015, 2389]. Gene disruption results in dyslipidemia and obesity [170].</td><td>Reported to act as a co-receptor for HIV [541]. In an infection-induced colitis model, Gpr15 knockout mice were more prone to tissue damage and inflammatory cytokine expression [1089].</td><td>Reported to be a dual leukotriene and uridine diphosphate receptor [395]. Another group instead proposed that GPR17 functions as a negative regulator of the CysLT<sub>1</sub> receptor response to leukotriene D<sub>4</sub> (LTD<sub>4</sub>). For further discussion, see [455]. Reported to antagonize CysLT<sub>1</sub> receptor signalling in vivo and in vitro [1350]. See reviews [280] and [455].</td></tr></table>

<table><tr><td>Nomenclature</td><td>GPR19</td><td>GPR20</td><td>GPR21</td><td>GPR22</td><td>GPR25</td><td>GPR26</td><td>GPR27</td></tr><tr><td>HGNC, UniProt</td><td>GPR19, Q15760</td><td>GPR20, Q99678</td><td>GPR21, Q99679</td><td>GPR22, Q99680</td><td>GPR25, O00155</td><td>GPR26, Q8NDV2</td><td>GPR27, Q9NS67</td></tr><tr><td>Agonists</td><td>adropin (ENHO, Q6UWT2) [1770]</td><td>–</td><td>–</td><td>–</td><td>–</td><td>–</td><td>–</td></tr><tr><td>Comments</td><td>–</td><td>Reported to inhibit adenylyl cyclase constitutively through G<sub>i/o</sub> [817]. GPR20 deficient mice exhibit hyperactivity characterised by increased total distance travelled in an open field test [230].</td><td>Gpr21 knockout mice were resistant to diet-induced obesity, exhibiting an increase in glucose tolerance and insulin sensitivity, as well as a modest lean phenotype [1639].</td><td>Gene disruption results in increased severity of functional decompensation following aortic banding [10]. Identified as a susceptibility locus for osteoarthritis [574, 1072, 2187].</td><td>–</td><td>Has been reported to activate adenylyl cyclase constitutively through G<sub>s</sub> [1016]. Gpr26 knockout mice show increased levels of anxiety and depression-like behaviours [2421].</td><td>Knockdown of Gpr27 reduces endogenous mouse insulin promoter activity and glucose-stimulated insulin secretion [1160].</td></tr></table>
<table><tr><td>Nomenclature</td><td>GPR31</td><td>GPR32</td><td>GPR33</td><td>GPR34</td></tr><tr><td>HGNC, UniProt</td><td>GPR31, O00270</td><td>GPR32, O75388</td><td>GPR33, Q49SQ1</td><td>GPR34, Q9UPC5</td></tr><tr><td>Potency order of endogenous ligands</td><td>–</td><td>resolvin D1 > LXA<sub>4</sub></td><td>–</td><td>–</td></tr><tr><td>Endogenous agonists</td><td>12S-HETE [769] – Mouse</td><td>resolvin D1 [1153], LXA<sub>4</sub> [1153]</td><td>–</td><td>lysophosphatidylserine [1107, 2054]</td></tr><tr><td>Labelled ligands</td><td>–</td><td>[<sup>3</sup>H]resolvin D1 (Agonist) [1153]</td><td>–</td><td>–</td></tr><tr><td>Comments</td><td>See [455] for discussion of pairing.</td><td>Resolvin D1 has been demonstrated to activate GPR32 in two publications [366, 1153]. The pairing was not replicated in a recent study based on arrestin recruitment [2015]. GPR32 is a pseudogene in mice and rats. See reviews [280] and [455].</td><td>GPR33 is a pseudogene in most individuals, containing a premature stop codon within the coding sequence of the second intracellular loop [1845].</td><td>Lysophosphatidylserine has been reported to be a ligand of GPR34 in several publications, but the pairing was not replicated in a recent study based on arrestin recruitment [2015]. Fails to respond to a variety of lipid-derived agents [2389]. Gene disruption results in an enhanced immune response [1277]. Characterization of agonists at this receptor is discussed in [945] and [455].</td></tr></table>

<table><tr><td>Nomenclature</td><td>GPR35</td><td>GPR37</td></tr><tr><td>HGNC, UniProt</td><td>GPR35, Q9HC97</td><td>GPR37, O15354</td></tr><tr><td>Endogenous agonists</td><td>2-oleoyl-LPA [1626], kynurenic acid [2015, 2253]</td><td>–</td></tr><tr><td>Agonists</td><td>–</td><td>neuropeptide head activator [1795]</td></tr><tr><td>Comments</td><td>Several studies have shown that kynurenic acid is an agonist of GPR35 but it remains controversial whether the proposed endogenous ligand reaches sufficient tissue concentrations to activate the receptor [1162]. 2-oleoyl-LPA has also been proposed as an endogenous ligand [1626] but these results were not replicated in an arrestin assay [2015]. The phosphodiesterase inhibitor zaprinast [2105] has become widely used as a surrogate agonist to investigate GPR35 pharmacology and signalling [2105]. GPR35 is also activated by the pharmaceutical adjunct pamoic acid [2432]. See reviews [455] and [502].</td><td>Reported to associate and regulate the dopamine transporter [1382] and to be a substrate for parkin [1380]. Gene disruption results in altered striatal signalling [1381]. The peptides prosapte and prosaposin are proposed as endogenous ligands for GPR37 and GPR37L1 [1438].</td></tr></table>
<table><tr><td>Nomenclature</td><td>GPR37L1</td><td>GPR39</td><td>GPR45</td><td>GPR50</td></tr><tr><td>HGNC, UniProt</td><td>GPR37L1, O60883</td><td>GPR39, O43194</td><td>GPR45, Q9Y5Y3</td><td>GPR50, Q13585</td></tr><tr><td>Endogenous agonists</td><td>–</td><td>Zn<sup>2+</sup> [898]</td><td>–</td><td>–</td></tr><tr><td>Comments</td><td>The peptides prosapptide and prosaposin are proposed as endogenous ligands for GPR37 and GPR37L1 [1438].</td><td>Zn<sup>2+</sup> has been reported to be a potent and efficacious agonist of human, mouse and rat GPR39 [2383]. Obestatin (GHRL, Q9UBU3), a fragment from the ghrelin precursor, was reported initially as an endogenous ligand, but subsequent studies failed to reproduce these findings. GPR39 has been reported to be down-regulated in adipose tissue in obesity-related diabetes [315]. Gene disruption results in obesity and altered adipocyte metabolism [1696]. Reviewed in [455].</td><td>–</td><td>GPR50 is structurally related to MT<sub>1</sub> and MT<sub>2</sub> melatonin receptors, with which it heterodimerises constitutively and specifically [1265]. Gpr50 knockout mice display abnormal thermoregulation and are much more likely than wild-type mice to enter fasting-induced torpor [126].</td></tr></table>

<table><tr><td>Nomenclature</td><td>GPR52</td><td>GPR61</td><td>GPR62</td><td>GPR63</td></tr><tr><td>HGNC, UniProt</td><td>GPR52, Q9Y2T5</td><td>GPR61, Q9BZJ8</td><td>GPR62, Q9BZJ7</td><td>GPR63, Q9BZJ6</td></tr><tr><td>Comments</td><td>First small molecule agonist reported [1931].</td><td>GPR61 deficient mice exhibit obesity associated with hyperphagia [1545]. Although no endogenous ligands have been identified, 5-(nonyloxy)tryptamine has been reported to be a low affinity inverse agonist [2092].</td><td>–</td><td>Sphingosine 1-phosphate and dioleoylphosphatidic acid have been reported to be low affinity agonists for GPR63 [1584] but this finding was not replicated in an arrestin-based assay [2389].</td></tr></table>

<table><tr><td>Nomenclature</td><td>GPR65</td><td>GPR68</td></tr><tr><td>HGNC, UniProt</td><td>GPR65, Q8IYL9</td><td>GPR68, Q15743</td></tr><tr><td>Endogenous ligands</td><td>Protons</td><td>Protons</td></tr><tr><td>Allosteric modulators</td><td>–</td><td>ogerin (Positive) (pK<sub>B</sub> 5) [925], lorazepam (Positive) [925]</td></tr><tr><td>Comments</td><td>GPR4, GPR65, GPR68 and GPR132 are now thought to function as proton-sensing receptors detecting acidic pH [455, 1932]. Reported to activate adenylate cyclase; gene disruption leads to reduced eosinophilia in models of allergic airway disease [1145].</td><td>GPR68 was previously identified as a receptor for sphingosylphosphorylcholine (SPC) [2358], but the original publication has been retracted [2357]. GPR4, GPR65, GPR68 and GPR132 are now thought to function as proton-sensing receptors detecting acidic pH [455, 1932]. A family of 3,5-disubstituted isoxazoles were identified as agonists of GPR68 [1839].</td></tr></table>
<table><tr><td>Nomenclature</td><td>GPR75</td><td>GPR78</td><td>GPR79</td><td>GPR82</td></tr><tr><td>HGNC, UniProt</td><td>GPR75, Q95800</td><td>GPR78, Q96P69</td><td>GPR79, -</td><td>GPR82, Q96P67</td></tr><tr><td>Comments</td><td>CCL5 (CCL5, P13501) was reported to be an agonist of GPR75 [942], but the pairing could not be repeated in an arrestin assay [2015].</td><td>GPR78 has been reported to be constitutively active, coupled to elevated cAMP production [1016].</td><td>-</td><td>Mice with Gpr82 knockout have a lower body weight and body fat content associated with reduced food intake, decreased serum triglyceride levels, as well as higher insulin sensitivity and glucose tolerance [558].</td></tr></table>

<table><tr><td>Nomenclature</td><td>GPR83</td><td>GPR84</td><td>GPR85</td><td>GPR87</td><td>GPR88</td><td>GPR101</td></tr><tr><td>HGNC, UniProt</td><td>GPR83, Q9NYM4</td><td>GPR84, Q9NQ55</td><td>GPR85, P60893</td><td>GPR87, Q9BY21</td><td>GPR88, Q9GZN0</td><td>GPR101, Q96P66</td></tr><tr><td>Endogenous agonists</td><td>-</td><td>-</td><td>-</td><td>LPA [1523, 2076]</td><td>-</td><td>-</td></tr><tr><td>Agonists</td><td>PEN (Mouse) [719] –<br/>Mouse, Zn<sup>2+</sup> [1531] –<br/>Mouse</td><td>decanoic acid [2015, 2254],<br/>undecanoic acid [2254],<br/>lauric acid [2254]</td><td>-</td><td>-</td><td>-</td><td>-</td></tr><tr><td>Comments</td><td>One isoform has been<br/>implicated in the induction<br/>of CD4(+) CD25(+)<br/>regulatory T cells (Tregs)<br/>during inflammatory<br/>immune responses [803].<br/>The extracellular N-terminal<br/>domain is reported as an<br/>intramolecular inverse<br/>agonist [1532].</td><td>Medium chain free fatty<br/>acids with carbon chain<br/>lengths of 9-14 activate<br/>GPR84 [2064, 2254]. A<br/>surrogate ligand for GPR84,<br/>6-n-octylaminouracil has<br/>also been proposed [2064].<br/>See review [455] for<br/>discussion of classification.<br/>Mutational analysis and<br/>molecular modelling of<br/>GPR84 has been reported<br/>[1588].</td><td>Proposed to regulate<br/>hippocampal neurogenesis<br/>in the adult, as well as<br/>neurogenesis-dependent<br/>learning and memory [352].</td><td>-</td><td>Gene disruption results in<br/>altered striatal signalling<br/>[1312]. Small molecule<br/>agonists have been reported<br/>[163].</td><td>Mutations in GPR101 have<br/>been linked to gigantism<br/>and acromegaly [2154].</td></tr></table>
<table><tr><td>Nomenclature</td><td>GPR132</td><td>GPR135</td><td>GPR139</td><td>GPR141</td><td>GPR142</td><td>GPR146</td></tr><tr><td>HGNC, UniProt</td><td>GPR132, Q9UNW8</td><td>GPR135, Q8IZ08</td><td>GPR139, Q6DWJ6</td><td>GPR141, Q7Z602</td><td>GPR142, Q7Z601</td><td>GPR146, Q96CH1</td></tr><tr><td>Endogenous ligands</td><td>Protons</td><td>–</td><td>–</td><td>–</td><td>–</td><td>–</td></tr><tr><td>Comments</td><td>GPR4, GPR65, GPR68 and GPR132 are now thought to function as proton-sensing receptors detecting acidic pH [455, 1932]. Reported to respond to lysophosphatidylcholine [1027], but later retracted [2321].</td><td>–</td><td>Peptide agonists have been reported [953].</td><td>–</td><td>Small molecule agonists have been reported [2138, 2407].</td><td>Yosten et al. demonstrated inhibition of proinsulin C-peptide (INS, P01308)-induced stimulation of cFos expression following knockdown of GPR146 in KATO III cells, suggesting proinsulin C-peptide as an endogenous ligand of the receptor [2404].</td></tr></table>

<table><tr><td>Nomenclature</td><td>GPR148</td><td>GPR149</td><td>GPR150</td><td>GPR151</td><td>GPR152</td><td>GPR153</td><td>GPR160</td></tr><tr><td>HGNC, UniProt</td><td>GPR148, Q8TDV2</td><td>GPR149, Q86SP6</td><td>GPR150, Q8NGU9</td><td>GPR151, Q8TDV0</td><td>GPR152, Q8TDT2</td><td>GPR153, Q6NV75</td><td>GPR160, Q9UJ42</td></tr><tr><td>Comments</td><td>–</td><td>Gpr149 knockout mice displayed increased fertility and enhanced ovulation, with increased levels of FSH receptor and cyclin D2 mRNA levels [542].</td><td>–</td><td>GPR151 responded to galanin with an EC50 value of 2 µM, suggesting that the endogenous ligand shares structural features with galanin (GAL, P22466) [939].</td><td>–</td><td>–</td><td>–</td></tr></table>
<table><tr><td>Nomenclature</td><td>GPR161</td><td>GPR162</td><td>GPR171</td><td>GPR173</td></tr><tr><td>HGNC, UniProt</td><td>GPR161, Q8N6U8</td><td>GPR162, Q16538</td><td>GPR171, O14626</td><td>GPR173, Q9NS66</td></tr><tr><td>Comments</td><td>A C-terminal truncation (deletion) mutation in Gpr161 causes congenital cataracts and neural tube defects in the vacuolated lens (vl) mouse mutant [1403]. The mutated receptor is associated with cataract, spina bifida and white belly spot phenotypes in mice [1140]. Gene disruption is associated with a failure of asymmetric embryonic development in zebrafish [1261].</td><td>–</td><td>GPR171 has been shown to be activated by the endogenous peptide BigLEN (Mouse). This receptor-peptide interaction is believed to be involved in regulating feeding and metabolism responses [718].</td><td>–</td></tr></table>

<table><tr><td>Nomenclature</td><td>GPR174</td><td>GPR176</td><td>GPR182</td><td>GPR183</td></tr><tr><td>HGNC, UniProt</td><td>GPR174, Q9BXC1</td><td>GPR176, Q14439</td><td>GPR182, O15218</td><td>GPR183, P32249</td></tr><tr><td>Endogenous agonists</td><td>lysophosphatidylserine [949]</td><td>–</td><td>–</td><td>7α,25-dihydroxycholesterol [799, 1301],<br>7α,27-dihydroxycholesterol [1301],<br>7β, 25-dihydroxycholesterol [1301],<br>7β, 27-dihydroxycholesterol [1301]</td></tr><tr><td>Comments</td><td>See [945] which discusses<br>characterization of agonists at this<br>receptor.</td><td>–</td><td>Rat GPR182 was first proposed as the<br>adrenomedullin receptor [1041].<br>However, it was later reported that rat<br>and human GPR182 did not respond to<br>adrenomedullin [1070] and GPR182 is<br>not currently considered to be a genuine<br>adrenomedullin receptor [831].</td><td>Two independent publications have<br>shown that 7α,25-dihydroxycholesterol<br>is an agonist of GPR183 and have<br>demonstrated by mass spectrometry<br>that this oxysterol is present<br>endogenously in tissues [799, 1301].<br>Gpr183-deficient mice show a reduction<br>in the early antibody response to a<br>T-dependent antigen. GPR183-deficient<br>B cells fail to migrate to the outer follicle<br>and instead stay in the follicle centre<br>[1062, 1685].</td></tr></table>
<table><tr><td>Nomenclature</td><td>LGR4</td><td>LGR5</td><td>LGR6</td></tr><tr><td>HGNC, UniProt</td><td>LGR4, Q9BXB1</td><td>LGR5, O75473</td><td>LGR6, Q9HBX8</td></tr><tr><td>Endogenous agonists</td><td>R-spondin-2 (RSP02, Q6UXX9) [305], R-spondin-1 (RSP01, Q2MKA7) [305], R-spondin-3 (RSP03, Q9BXY4) [305], R-spondin-4 (RSP04, Q2I0M5) [305]</td><td>R-spondin-2 (RSP02, Q6UXX9) [305], R-spondin-1 (RSP01, Q2MKA7) [305], R-spondin-3 (RSP03, Q9BXY4) [305], R-spondin-4 (RSP04, Q2I0M5) [305]</td><td>R-spondin-1 (RSP01, Q2MKA7) [305, 467], R-spondin-2 (RSP02, Q6UXX9) [305, 467], R-spondin-3 (RSP03, Q9BXY4) [305, 467], R-spondin-4 (RSP04, Q2I0M5) [305, 467]</td></tr><tr><td>Comments</td><td>LGR4 does not couple to heterotrimeric G proteins or recruit arrestins when stimulated by the R-spondins, indicating a unique mechanism of action. R-spondins bind to LGR4, which specifically associates with Frizzled and LDL receptor-related proteins (LRPs) that are activated by the extracellular Wnt molecules and then trigger canonical Wnt signalling to increase gene expression [305, 467, 1834]. Gene disruption leads to multiple developmental disorders [1002, 1329, 2011, 2284].</td><td>The four R-spondins can bind to LGR4, LGR5, and LGR6, which specifically associate with Frizzled and LDL receptor-related proteins (LRPs), proteins that are activated by extracellular Wnt molecules and which then trigger canonical Wnt signalling to increase gene expression [305, 467].</td><td>–</td></tr></table>

<table><tr><td>Nomenclature</td><td>MAS1</td><td>MAS1L</td></tr><tr><td>HGNC, UniProt</td><td>MAS1, P04201</td><td>MAS1L, P35410</td></tr><tr><td>Agonists</td><td>angiotensin-(1-7) (AGT, P01019) [707] – Mouse</td><td>–</td></tr></table>

<table><tr><td>Nomenclature</td><td>MRGPRD</td><td>MRGPRE</td><td>MRGPRF</td><td>MRGPRG</td></tr><tr><td>HGNC, UniProt</td><td>MRGPRD, Q8TDS7</td><td>MRGPRE, Q86SM8</td><td>MRGPRF, Q96AM1</td><td>MRGPRG, Q86SM5</td></tr><tr><td>Endogenous agonists</td><td>β-alanine [1958, 2015]</td><td>–</td><td>–</td><td>–</td></tr><tr><td>Comments</td><td>An endogenous peptide with a high degree of sequence similarity to angiotensin-(1-7) (AGT, P01019), alamandine (AGT), was shown to promote NO release in MRGPRD-transfected cells. The binding of alamandine to MRGPRD to was shown to be blocked by D-Pro<sup>7</sup>-angiotensin-(1-7), β-alanine and PD123319 [1208]. Genetic ablation of MRGPRD+ neurons of adult mice decreased behavioural sensitivity to mechanical stimuli but not to thermal stimuli [322]. See reviews [455] and [2009].</td><td>See reviews [455] and [2009].</td><td>MRGPRF has been reported to respond to stimulation by angiotensin metabolites [678]. See reviews [455] and [2009].</td><td>See reviews [455] and [2009].</td></tr></table>
<table><tr><td>Nomenclature</td><td>MRGPRX1</td><td>MRGPRX2</td><td>MRGPRX3</td><td>MRGPRX4</td><td>P2RY8</td><td>P2RY10</td></tr><tr><td>HGNC, UniProt</td><td>MRGPRX1, Q96LB2</td><td>MRGPRX2, Q96LB1</td><td>MRGPRX3, Q96LB0</td><td>MRGPRX4, Q96LA9</td><td>P2RY8, Q86VZ1</td><td>P2RY10, O00398</td></tr><tr><td>Endogenous agonists</td><td>bovine adrenal medulla peptide 8-22 (PENK, P01210) [347, 1253, 2015]</td><td>PAMP-20 (ADM, P35318) [1035]</td><td>–</td><td>–</td><td>–</td><td>sphingosine 1-phosphate [1523], LPA [1523]</td></tr><tr><td>Agonists</td><td>–</td><td>cortistatin-14 (Mouse, Rat) [1035, 1202, 1815, 2015]</td><td>–</td><td>–</td><td>–</td><td>–</td></tr><tr><td>Selective agonists</td><td>–</td><td>PAMP-12 (human) [1035]</td><td>–</td><td>–</td><td>–</td><td>–</td></tr><tr><td>Comments</td><td>Reported to mediate the sensation of itch [1305, 1969]. Reports that bovine adrenal medulla peptide 8-22 (PENK, P01210) was the most potent of a series of proenkephalin A-derived peptides as an agonist of MRGPRX1 in assays of calcium mobilisation and radioligand binding [1253] were replicated in an independent study using an arrestin recruitment assay [2015]. See reviews [455] and [2009].</td><td>A diverse range of substances has been reported to be agonists of MRGPRX2, with cortistatin 14 the highest potency agonist in assays of calcium mobilisation [1815], also confirmed in an independent study using an arrestin recruitment assay [2015]. See reviews [455] and [2009].</td><td>–</td><td>See reviews [455] and [2009].</td><td>–</td><td>–</td></tr></table>

<table><tr><td>Nomenclature</td><td>TAAR2</td><td>TAAR3</td><td>TAAR4P</td><td>TAAR5</td><td>TAAR6</td><td>TAAR8</td><td>TAAR9</td></tr><tr><td>HGNC, UniProt</td><td>TAAR2, Q9P1P5</td><td>TAAR3P, Q9P1P4</td><td>TAAR4P, –</td><td>TAAR5, O14804</td><td>TAAR6, Q96RI8</td><td>TAAR8, Q969N4</td><td>TAAR9, Q96RI9</td></tr><tr><td>Potency order of endogenous ligands</td><td>β-phenylethylamine > tryptamine [205]</td><td>–</td><td>–</td><td>–</td><td>–</td><td>–</td><td>–</td></tr><tr><td>Comments</td><td>Probable pseudogene in 10–15% of Asians due to a polymorphism (rs8192646) producing a premature stop codon at amino acid 168 [455].</td><td>TAAR3 is thought to be a pseudogene in man though functional in rodents [455].</td><td>Pseudogene in man but functional in rodents [455].</td><td>Trimethylamine is reported as an agonist [2242] and 3-iodothyronamine an inverse agonist [499].</td><td>–</td><td>–</td><td>TAAR9 appears to be functional in most individuals but has a polymorphic premature stop codon at amino acid 61 (rs2842899) with an allele frequency of 10–30% in different populations [2202].</td></tr></table>

Further reading on Class A Orphans

McNeil BD et al. (2015) Identification of a mast-cell-specific receptor crucial for pseudo-allergic drug reactions. *Nature* **519**: 237-41 [PMID:25517090]
# Class C Orphans

G protein-coupled receptors → Orphan and other 7TM receptors → Class C Orphans

**Overview:** This set contains class C 'orphan' G protein coupled receptors where the endogenous ligand(s) is not known.

<table><tr><td>Nomenclature</td><td>GPR156</td><td>GPR158</td><td>GPR179</td><td>GPRC5A</td><td>GPRC5B</td><td>GPRC5C</td><td>GPRC5D</td><td>GPRC6 receptor</td></tr><tr><td>HGNC, UniProt</td><td>GPR156, Q8NFN8</td><td>GPR158, Q5T848</td><td>GPR179, Q6PRD1</td><td>GPRC5A, Q8NFJ5</td><td>GPRC5B, Q9NZH0</td><td>GPRC5C, Q9NQ84</td><td>GPRC5D, Q9NZD1</td><td>GPRC6A, Q5T6X5</td></tr><tr><td>Comments</td><td>-</td><td>-</td><td>-</td><td>-</td><td>-</td><td>-</td><td>-</td><td>GPRC6 is a G<sub>q</sub>-coupled receptor which responds to basic amino acids [2282].</td></tr></table>

## Further reading on Class C Orphans

Harpse *K et al.* (2017) Structural insight to mutation effects uncover a common allosteric site in class C GPCRs. *Bioinformatics* **33**: 1116-1120 [PMID:28011766]

# Taste 1 receptors

G protein-coupled receptors → Orphan and other 7TM receptors → Taste 1 receptors

**Overview:** Whilst the taste of acid and salty foods appear to be sensed by regulation of ion channel activity, bitter, sweet and umami tastes are sensed by specialised GPCR. Two classes of taste GPCR have been identified, T1R and T2R, which are similar in sequence and structure to Class C and Class A GPCR, respectively. Activation of taste receptors appears to involve gustducin- (Gαt3) and Gα14-mediated signalling, although the precise mechanisms

remain obscure. Gene disruption studies suggest the involvement of PLCβ2 [2429], TRPM5 [2429] and IP3 [883] receptors in post-receptor signalling of taste receptors. Although predominantly associated with the oral cavity, taste receptors are also located elsewhere, including further down the gastrointestinal system, in the lungs and in the brain.

**Sweet/Umami:** T1R3 acts as an obligate partner in T1R1/T1R3 and T1R2/T1R3 heterodimers, which sense umami or sweet, respectively. T1R1/T1R3 heterodimers respond to L-glutamic acid and may be positively allosterically modulated by 5'-nucleoside monophosphates, such as 5'-GMP [1272]. T1R2/T1R3 heterodimers respond to sugars, such as sucrose, and artificial sweeteners, such as saccharin [1564].

<table><tr><td>Nomenclature</td><td>TAS1R1</td><td>TAS1R2</td><td>TAS1R3</td></tr><tr><td>HGNC, UniProt</td><td>TAS1R1, Q7RTX1</td><td>TAS1R2, Q8TE23</td><td>TAS1R3, Q7RTX0</td></tr></table>

**Comments:** Positive allosteric modulators of T1R2/T1R3 have been reported [2363]. Such compounds enhance the sweet taste of sucrose mediated by these receptors, but are tasteless on their own.
Further reading on Taste 1 receptors

Palmer RK. (2019) A Pharmacological Perspective on the Study of Taste. *Pharmacol. Rev.* **71**: 20-48
[PMID:30559245]

Taste 2 receptors

G protein-coupled receptors → Orphan and other 7TM receptors → Taste 2 receptors

**Overview:** The composition and stoichiometry of bitter taste receptors is not yet established. Bitter receptors appear to separate into two groups, with very restricted ligand specificity or much broader responsiveness. For example, T2R5 responded to *cycloheximide*, but not 10 other bitter compounds [334], while T2R14 responded to at least eight different bitter tastants, including (-)-*α*-thujone and *picrotoxinin* [133].

Specialist database BitterDB contains additional information on bitter compounds and receptors [2306].

Nomenclature
HGNC, UniProt

TAS2R1
TAS2R1, Q9NYW7

TAS2R3
TAS2R3, Q9NYW6

TAS2R4
TAS2R4, Q9NYW5

TAS2R5
TAS2R5, Q9NYW4

TAS2R7
TAS2R7, Q9NYW3

TAS2R8
TAS2R8, Q9NYW2

TAS2R9
TAS2R9, Q9NYW1

Nomenclature
HGNC, UniProt

TAS2R10
TAS2R10, Q9NYW0

TAS2R13
TAS2R13, Q9NYV9

TAS2R14
TAS2R14, Q9NYV8

TAS2R16
TAS2R16, Q9NYV7

TAS2R19
TAS2R19, P59542

TAS2R20
TAS2R20, P59543

TAS2R30
TAS2R30, P59541

Nomenclature
HGNC, UniProt
Antagonists

TAS2R31
TAS2R31, P59538

TAS2R38
TAS2R38, P59533

TAS2R39
TAS2R39, P59534

TAS2R40
TAS2R40, P59535

6-methoxysakuranetin (pIC₅₀ 5.6) [1098],
GIV3727 (pIC₅₀ 5.1–5.2) [1984]

–
–
–
<table><tr><td>Nomenclature</td><td>TAS2R41</td><td>TAS2R42</td><td>TAS2R43</td><td>TAS2R45</td><td>TAS2R46</td><td>TAS2R50</td><td>TAS2R60</td></tr><tr><td>HGNC, UniProt</td><td>TAS2R41, P59536</td><td>TAS2R42, Q7RTR8</td><td>TAS2R43, P59537</td><td>TAS2R45, P59539</td><td>TAS2R46, P59540</td><td>TAS2R50, P59544</td><td>TAS2R60, P59551</td></tr></table>

Further reading on Taste 2 receptors

Palmer RK. (2019) A Pharmacological Perspective on the Study of Taste. *Pharmacol. Rev.* **71**: 20-48 [PMID:30559245]

Other 7TM proteins

G protein-coupled receptors → Orphan and other 7TM receptors → Other 7TM proteins

<table><tr><td>Nomenclature</td><td>GPR107</td><td>GPR137</td><td>TPRA1</td><td>GPR143</td><td>GPR157</td></tr><tr><td>HGNC, UniProt</td><td>GPR107, Q5VW38</td><td>GPR137, Q96N19</td><td>TPRA1, Q86W33</td><td>GPR143, P51810</td><td>GPR157, Q5UAW9</td></tr><tr><td>Endogenous agonists</td><td>–</td><td>–</td><td>–</td><td>levodopa [1316]</td><td>–</td></tr><tr><td>Comments</td><td>GPR107 is a member of the Lustr family of proteins found in both plants and animals, having similar topology to G protein-coupled receptors [540]</td><td>–</td><td>TPRA1 shows no homology to known G protein-coupled receptors.</td><td>Loss-of-function mutations underlie ocular albinism type 1 [117].</td><td>GPR157 has ambiguous sequence similarities to several different GPCR families (class A, class B and the slime mould cyclic AMP receptor). Because of its distant relationship to other GPCRs, it cannot be readily classified.</td></tr></table>

Further reading on Orphan and other 7TM receptors

Davenport AP *et al*. (2013) International Union of Basic and Clinical Pharmacology. LXXXVIII. G protein-coupled receptor list: recommendations for new pairings with cognate ligands. *Pharmacol. Rev.* **65**: 967-86 [PMID:23686350]

Gilissen J *et al*. (2016) Insight into SUCNR1 (GPR91) structure and function. *Pharmacol. Ther.* **159**: 56-65 [PMID:26808164]

Insel PA *et al*. (2015) G Protein-Coupled Receptor (GPCR) Expression in Native Cells: "Novel" endoGPCRs as Physiologic Regulators and Therapeutic Targets. *Mol. Pharmacol.* **88**: 181-7 [PMID:25737495]

Khan MZ *et al*. (2017) Neuro-psychopharmacological perspective of Orphan receptors of Rhodopsin (class A) family of G protein-coupled receptors. *Psychopharmacology (Berl.)* **234**: 1181-1207 [PMID:28289782]

Mackenzie AE *et al*. (2017) The emerging pharmacology and function of GPR35 in the nervous system. *Neuropharmacology* **113**: 661-671 [PMID:26232640]

Ngo T *et al*. (2016) Identifying ligands at orphan GPCRs: current status using structure-based approaches. *Br. J. Pharmacol.* **173**: 2934-51 [PMID:26837045]
# 5-Hydroxytryptamine receptors

G protein-coupled receptors → 5-Hydroxytryptamine receptors

**Overview:** 5-HT receptors (nomenclature as agreed by the **NC-IUPHAR Subcommittee on 5-HT receptors [914]** and **subsequently revised [816]**)) are, with the exception of the ionotropic 5-HT₃ class, GPCRs where the endogenous agonist is **5-hydroxytryptamine**. The diversity of metabotropic 5-HT receptors is increased by alternative splicing that produces isoforms of the 5-HT₂A (non-functional), 5-HT₂C (non-functional), 5-HT₄, 5-HT₆ (non-functional) and 5-HT₇ receptors. Unique amongst the GPCRs, RNA editing produces 5-HT₂C receptor isoforms that differ in function, such as efficiency and specificity of coupling to

Gq/11 and also pharmacology [181, 2291]. Most 5-HT receptors (except 5-ht₁e and 5-ht₅b) play specific roles mediating functional responses in different tissues (reviewed by [1765, 2219]).

Nomenclature 5-HT₁A receptor

HGNC, UniProt HTR1A, P08908

Agonists U92016A [1416], vilazodone (Partial agonist) [463], vortioxetine (Partial agonist) [105]

Selective agonists 8-OH-DPAT [473, 791, 1032, 1251, 1452, 1575, 1577, 1578], NLX-101 [1576]

Antagonists (S)-UH 301 (pKᵢ 7.9) [1575]

Selective antagonists WAY-100635 (pKᵢ 7.9–9.2) [1575, 1577], robalzotan (pKᵢ 9.2) [1007]

Labelled ligands [³H]robalzotan (Antagonist) (pK₉ 9.8) [994], [³H]WAY100635 (Antagonist) (pK₉ 9.5) [1075], [³H]8-OH-DPAT (Agonist) [174, 1032, 1574, 1577], [³H]NLX-112 (Agonist) [864], [¹¹C]WAY100635 (Antagonist) [2161], p-[¹⁸F]MPPF (Antagonist) [418]

5-HT₁B receptor

HTR1B, P28222

L-694,247 [738], naratriptan (Partial agonist) [1548], eletriptan [1548], frovatriptan [2359], zolmitriptan (Partial agonist) [1548], vortioxetine (Partial agonist) [105], rizatriptan (Partial agonist) [1548]

CP94253 [1122]

SB 224289 (Inverse agonist) (pKᵢ 8.2–8.6) [670, 1573, 1924], SB236057 (Inverse agonist) (pKᵢ 8.2) [1445], GR-55562 (pK₉ 7.4) [915]

[³H]N-methyl-AZ10419369 (Agonist, Partial agonist) [1356], [³H]GR 125,743 (Selective Antagonist) (pK₉ 8.6–9.2) [738, 2350], [³H]alniditan (Agonist) [1260], [¹²⁵I]GTI (Agonist) [213, 256] – Rat, [³H]eletriptan (Agonist, Partial agonist) [1548], [³H]sumatriptan (Agonist, Partial agonist) [1548], [¹¹C]AZ10419369 (Agonist, Partial agonist) [2207]
<table><tr><td>Nomenclature</td><td>5-HT<sub>1D</sub> receptor</td><td>5-ht<sub>1e</sub> receptor</td><td>5-HT<sub>1F</sub> receptor</td></tr><tr><td>HGNC, UniProt</td><td>HTR1D, P28221</td><td>HTR1E, P28566</td><td>HTR1F, P30939</td></tr><tr><td>Agonists</td><td>dihydroergotamine [790, 1260, 1267], ergotamine [711], L-694,247 [2340], naratriptan [506, 1548, 1794], zolmitriptan [1548], frovatriptan [2359], rizatriptan [1548]</td><td>BRL-54443 [250]</td><td>BRL-54443 [250], eletriptan [1548], sumatriptan [12, 13, 1548, 2236]</td></tr><tr><td>Selective agonists</td><td>PNU109291 [564] – Gorilla, eletriptan [1548]</td><td>–</td><td>lasmiditan [1563], LY334370 [2236], 5-BODMT [1113], LY344864 [1702]</td></tr><tr><td>Selective antagonists</td><td>SB 714786 (pK<sub>i</sub> 9.1) [2264]</td><td>–</td><td>–</td></tr><tr><td>Labelled ligands</td><td>[<sup>3</sup>H]eletriptan (Agonist) [1548], [<sup>3</sup>H]alniditan (Agonist) [1260], [<sup>125</sup>I]GTI (Selective Agonist) [213, 256] – Rat, [<sup>3</sup>H]GR 125,743 (Selective Antagonist) (pK<sub>d</sub> 8.6) [2350], [<sup>3</sup>H]sumatriptan (Agonist) [1548]</td><td>[<sup>3</sup>H]5-HT (Agonist) [1413, 1657]</td><td>[<sup>3</sup>H]LY334370 (Agonist) [2236], [<sup>125</sup>I]LSD (Agonist) [48] – Mouse</td></tr></table>

<table><tr><td>Nomenclature</td><td>5-HT<sub>2A</sub> receptor</td><td>5-HT<sub>2B</sub> receptor</td><td>5-HT<sub>2C</sub> receptor</td></tr><tr><td>HGNC, UniProt</td><td>HTR2A, P28223</td><td>HTR2B, P41595</td><td>HTR2C, P28335</td></tr><tr><td>Agonists</td><td>DOI [227, 1562, 1986]</td><td>methylsergide (Partial agonist) [1117, 1827, 2237], DOI [1179, 1562, 1883]</td><td>DOI [544, 1562, 1883], Ro 60-0175 [1097, 1117]</td></tr><tr><td>Selective agonists</td><td>–</td><td>BW723C86 [124, 1117, 1883], Ro 60-0175 [1117]</td><td>WAY-163909 [533], lorcaserin [2125]</td></tr><tr><td>Antagonists</td><td>risperidone (Inverse agonist) (pK<sub>i</sub> 9.3–10) [1131, 1156, 1901], mianserin (pK<sub>i</sub> 7.7–9.6) [1117, 1146, 1452], ziprasidone (pK<sub>i</sub> 8.8–9.5) [1131, 1156, 1901, 1939], volinanserin (pIC<sub>50</sub> 6.5–9.3) [1117, 1317, 1782], blonanserin (pK<sub>i</sub> 9.1) [1611], clozapine (Inverse agonist) (pK<sub>i</sub> 7.6–9) [1117, 1156, 1449, 1901, 2201], H05 (pIC<sub>50</sub> 7.2) [2356]</td><td>mianserin (pK<sub>i</sub> 7.9–8.8) [200, 1117, 2237]</td><td>mianserin (Inverse agonist) (pK<sub>i</sub> 8.3–9.2) [607, 1117, 1452], methylsergide (pK<sub>i</sub> 8.6–9.1) [544, 1117], ziprasidone (Inverse agonist) (pK<sub>i</sub> 7.9–9) [858, 1156, 1939], olanzapine (Inverse agonist) (pK<sub>i</sub> 8.1–8.4) [858, 1156, 1939], loxapine (Inverse agonist) (pK<sub>i</sub> 7.8–8) [858, 1156]</td></tr><tr><td>Selective antagonists</td><td>compound 3b (pK<sub>i</sub> 10.6) [603], ketanserin (pK<sub>i</sub> 8.1–9.7) [261, 1117, 1771], pimavanserin (Inverse agonist) (pK<sub>i</sub> 9.3) [659, 2201]</td><td>BF-1 (pK<sub>i</sub> 10.1) [1895], RS-127445 (pK<sub>i</sub> 9–9.5) [200, 1117], EGIS-7625 (pK<sub>i</sub> 9) [1146]</td><td>FR260010 (pK<sub>i</sub> 9) [807], SB 242084 (pK<sub>i</sub> 8.2–9) [1071, 1117], RS-102221 (pK<sub>i</sub> 8.3–8.4) [201, 1117]</td></tr><tr><td>Labelled ligands</td><td>[<sup>3</sup>H]fananserin (Antagonist) (pK<sub>d</sub> 9.9) [1362] – Rat, [<sup>3</sup>H]ketanserin (Antagonist) (pK<sub>d</sub> 8.6–9.7) [1117, 1771], [<sup>11</sup>C]volinanserin (Antagonist) [784], [<sup>18</sup>F]altanserin (Antagonist) [1823]</td><td>[<sup>3</sup>H]LSD (Agonist) [1771], [<sup>3</sup>H]5-HT (Agonist) [2235] – Rat, [<sup>3</sup>H]mesulergine (Antagonist, Inverse agonist) (pK<sub>d</sub> 7.9) [1117], [<sup>125</sup>I]DOI (Agonist)</td><td>[<sup>3</sup>H]mesulergine (Antagonist, Inverse agonist) (pK<sub>d</sub> 8.7–9.3) [607, 1771], [<sup>125</sup>I]DOI (Agonist) [607], [<sup>3</sup>H]LSD (Agonist)</td></tr></table>
<table><tr><td>Nomenclature</td><td>5-HT<sub>4</sub> receptor</td><td>5-HT<sub>5A</sub> receptor</td><td>5-HT<sub>5b</sub> receptor</td></tr><tr><td>HGNC, UniProt</td><td>HTR4, Q13639</td><td>HTR5A, P47898</td><td>HTR5BP, –</td></tr><tr><td>Agonists</td><td>cisapride (Partial agonist) [89, 141, 690, 1440, 1441, 2190]</td><td></td><td></td></tr><tr><td>Selective agonists</td><td>TD-8954 [1427], ML 10302 (Partial agonist) [152, 178, 1440, 1441, 1442], RS67506 [842] – Rat, relenopride (Partial agonist) [702], velusetrag [1314, 1994], BIMU 8 [398]</td><td>–</td><td>–</td></tr><tr><td>Selective antagonists</td><td>RS 100235 (pK<sub>i</sub> 8.7–12.2) [398, 1809], SB 204070 (pK<sub>i</sub> 9.8–10.4) [141, 1440, 1441, 2192], GR 113808 (pK<sub>i</sub> 9.3–10.3) [89, 141, 178, 398, 1401, 1809, 2190]</td><td>SB 699551 (pK<sub>i</sub> 8.2) [416]</td><td>–</td></tr><tr><td>Labelled ligands</td><td>[<sup>3</sup>H]GR 113808 (Antagonist) (pK<sub>d</sub> 9.7–10.3) [89, 141, 1442, 2190], [<sup>123</sup>I]SB 207710 (Antagonist) (pK<sub>d</sub> 10.1) [251] – Pig, [<sup>3</sup>H]RS 57639 (Selective Antagonist) (pK<sub>d</sub> 9.7) [199] – Guinea pig, [<sup>11</sup>C]SB207145 (Antagonist) (pK<sub>d</sub> 8.6) [1344]</td><td>[<sup>125</sup>I]LSD (Agonist) [737], [<sup>3</sup>H]5-CT (Agonist) [737]</td><td>[<sup>125</sup>I]LSD (Agonist) [1404] – Mouse, [<sup>3</sup>H]5-CT (Agonist) [2233] – Mouse</td></tr></table>

<table><tr><td>Nomenclature</td><td>5-HT<sub>6</sub> receptor</td><td>5-HT<sub>7</sub> receptor</td></tr><tr><td>HGNC, UniProt</td><td>HTR6, P50406</td><td>HTR7, P34969</td></tr><tr><td>Selective agonists</td><td>WAY-181187 [1887], E6801 (Partial agonist) [893], WAY-208466 [151], EMD-386088 [1405]</td><td>LP-12 [1257], LP-44 [1257], LP-211 [1258] – Rat, AS-19 [1091], E55888 [229]</td></tr><tr><td>Antagonists</td><td>–</td><td>lurasidone (pK<sub>i</sub> 9.3) [954], pimozide (pK<sub>i</sub> 9.3) [1826] – Rat, vortioxetine (pK<sub>i</sub> 6.3) [105]</td></tr><tr><td>Selective antagonists</td><td>SB399885 (pK<sub>i</sub> 9) [882], SB 271046 (pK<sub>i</sub> 8.9) [247], cerlapirdine (pK<sub>i</sub> 8.9) [407], SB357134 (pK<sub>i</sub> 8.5) [248], Ro 63-0563 (pK<sub>i</sub> 7.9–8.4) [184, 1985]</td><td>SB269970 (pK<sub>i</sub> 8.6–8.9) [2119], SB656104 (pK<sub>i</sub> 8.7) [613], DR-4004 (pK<sub>i</sub> 8.7) [710, 1082], JNJ-18038683 (pK<sub>i</sub> 8.2) [197], SB 258719 (Inverse agonist) (pK<sub>i</sub> 7.5) [2120]</td></tr><tr><td>Labelled ligands</td><td>[<sup>11</sup>C]GSK215083 (Antagonist) (pK<sub>i</sub> 9.8) [1656], [<sup>125</sup>I]SB258585 (Selective Antagonist) (pK<sub>d</sub> 9) [882], [<sup>3</sup>H]LSD (Agonist) [183], [<sup>3</sup>H]Ro 63-0563 (Antagonist) (pK<sub>d</sub> 8.3) [184], [<sup>3</sup>H]5-CT (Agonist)</td><td>[<sup>3</sup>H]5-CT (Agonist) [2119], [<sup>3</sup>H]5-HT (Agonist) [107, 2026], [<sup>3</sup>H]SB269970 (Selective Antagonist) (pK<sub>d</sub> 8.9) [2119], [<sup>3</sup>H]LSD (Agonist) [2026]</td></tr></table>

**Comments:** Tabulated pK<sub>i</sub> and K<sub>d</sub> values refer to binding to human 5-HT receptors unless indicated otherwise. The nomenclature of 5-HT<sub>1B</sub>/5-HT<sub>1D</sub> receptors has been revised [816]. Only the non-rodent form of the receptor was previously called 5-HT<sub>1D</sub>: the human 5-HT<sub>1B</sub> receptor (tabulated) displays a different pharmacology to the rodent forms of the receptor due to Thr335 of the human sequence being replaced by Asn in rodent receptors [800]. Wang *et al.* (2013) report X-ray structures which reveal the binding modality of ergotamine and dihydroergotamine (DHE) to the 5-HT<sub>1B</sub> receptor in comparison with the structure of the 5-HT<sub>2B</sub> receptor [2249]; some of these drugs adopt rather different conformations depending on the target receptor [1681]. Various

5-HT receptors have multiple partners in addition to G proteins, which may affect function and pharmacology [1384]. NAS181 is a selective antagonist of the rodent 5-HT<sub>1B</sub> receptor. Fananserin (LSD) and ketanserin bind with high affinity to dopamine D4 and histamine H<sub>1</sub> receptors respectively, and ketanserin is a potent α1 adrenoceptor antagonist, in addition to blocking 5-HT<sub>2A</sub> receptors. Lysergic acid (LSD) and ergotamine show a strong preference for arrestin recruitment over G protein coupling at the 5-HT<sub>2B</sub> receptor, with no such preference evident at 5-HT<sub>1B</sub> receptors, and they also antagonise 5-HT<sub>7A</sub> receptors [2231]. DHE (dihydroergocryptine), pergolide and cabergoline also show significant preference for arrestin recruitment over G protein coupling at 5-HT<sub>2B</sub> receptors [2231].

The 5-HT<sub>2B</sub> (and other 5-HT) receptors interact with immunocompetent cells [1645]. The serotonin antagonist mesulergine was key to the discovery of the 5-HT<sub>2C</sub> receptor [1672], initially known as 5-HT1C [83]. The human 5-HT<sub>5A</sub> receptor may couple to several signal transduction pathways when stably expressed in C6 glioma cells [1599] and rodent prefrontal cortex (layer V pyramidal neurons) [724]. The human orthologue of the mouse 5-HT<sub>5b</sub> receptor is non-functional (stop codons); the 5-HT<sub>1e</sub> receptor has not been cloned from mouse, or rat, impeding definition of its function [800]. In addition to accepted receptors, an 'orphan' receptor, unofficially termed 5-HT<sub>1p</sub>, has been described [695].
Further reading on 5-Hydroxytryptamine receptors

Bockaert J et al. (2011) 5-HT(4) receptors, a place in the sun: act two. *Curr Opin Pharmacol* **11**: 87-93 [PMID:21342787]

Hayes DJ et al. (2011) 5-HT receptors and reward-related behaviour: a review. *Neurosci Biobehav Rev* **35**: 1419-49 [PMID:21402098]

Hoyer D et al. (1994) International Union of Pharmacology classification of receptors for 5-hydroxytryptamine (Serotonin). *Pharmacol. Rev.* **46**: 157-203 [PMID:7938165]

Leopoldo M et al. (2011) Serotonin 5-HT7 receptor agents: Structure-activity relationships and potential therapeutic applications in central nervous system disorders. *Pharmacol. Ther.* **129**: 120-48 [PMID:20923682]

Meltzer HY et al. (2011) The role of serotonin receptors in the action of atypical antipsychotic drugs. *Curr Opin Pharmacol* **11**: 59-67 [PMID:21420906]

Roberts AJ et al. (2012) The 5-HT(7) receptor in learning and memory. *Hippocampus* **22**: 762-71 [PMID:21484935]

Acetylcholine receptors (muscarinic)

G protein-coupled receptors → Acetylcholine receptors (muscarinic)

**Overview:** Muscarinic acetylcholine receptors (nomenclature as agreed by the NC-IUPHAR Subcommittee on Muscarinic Acetylcholine Receptors [318]) are GPCRs of the Class A, rhodopsin-like family where the endogenous agonist is acetylcholine. In addition to the agents listed in the ta-

ble, AC-42, its structural analogues AC-260584 and 77-LH-28-1, N-desmethylclozapine, TBPB and LuAE51090 have been described as functionally selective agonists of the M₁ receptor subtype via binding in a mode distinct from that utilized by non-selective agonists [82, 1014, 1198, 1199, 1408, 1859, 2018, 2019, 2061]. There

are two pharmacologically characterised allosteric sites on muscarinic receptors, one defined by its binding gallamine, strychnine and brucine, and the other defined by the binding of KT 5720, WIN 62,577, WIN 51,708 and staurosporine [1215, 1216].

Nomenclature M₁ receptor

M₂ receptor

HGNC, UniProt CHRM1, P11229

CHRM2, P08172

Agonists carbachol [385, 976, 2326], pilocarpine (Partial agonist) [976], bethanechol [976]

carbachol [358, 976, 1147], bethanechol [976]

Selective agonists SPP1 [242]

Antagonists glycopyrrolate (pIC₅₀ 9.9) [2037], AE9C90CB (pKᵢ 9.7) [1979], atropine (pKᵢ 8.5–9.6) [385, 636, 878, 923, 1683, 1993], tiotropium (pKᵢ 9.6) [501], 4-DAMP (pKᵢ 9.2) [537]

tiotropium (pKᵢ 9.9) [501], glycopyrrolate (pIC₅₀ 9.3) [2037], atropine (pKᵢ 7.8–9.2) [265, 358, 878, 923, 1147, 1561, 1683], AE9C90CB (pKᵢ 8.6) [1979], tolterodine (Inverse agonist) (pKᵢ 8.4–8.6) [704, 1561, 1979]

Selective antagonists biperiden (pK₉ 9.3) [190], VU0255035 (pKᵢ 7.8) [1943], guanylpirenzepine (pKᵢ 7.3–7.6) [25, 2234] – Rat

tripitramine (pKᵢ 9.6) [1351]

Allosteric modulators muscarinic toxin 7 (Negative) (pKᵢ 11–11.1) [1606], benzoquinazolinone 12 (Positive) (pK₉ 6.6) [4], KT 5720 (Positive) (pK₉ 6.4) [1215], brucine (Positive) (pK₉ 4.5–5.8) [976, 1214], BQCA (Positive) (pK₉ 4–4.8) [4, 5, 296, 1336], VU0029767 (Positive) [1385], VU0090157 (Positive) [1385]

W-84 (Negative) (pK₉ 6–7.5) [1470, 2155], C₇/3-phth (Negative) (pK₉ 7.1) [386], alcuronium (Negative) (pK₉ 6.1–6.9) [976, 2155], gallamine (Negative) (pK₉ 5.9–6.3) [399, 1212], LY2119620 (Positive) (pK₉ 5.7) [437, 1158], LY2033298 (Positive) (pK₉ 4.4) [2185]

Labelled ligands [³H]QNB (Antagonist) (pK₉ 10.6–10.8) [387, 1683], Cy3B-telenzepine (Antagonist) (pK₉ 10.5) [856], [³H]N-methyl scopolamine (Antagonist) (pK₉ 9.4–10.3) [324, 385, 387, 878, 976, 977, 1011, 1074, 1212], [³H](+)telenzepine (Antagonist) (pKᵢ 9.4) [580] – Rat, Alexa-488-telenzepine (Antagonist) (pK₉ 9.3) [856], [³H]pirenzepine (Antagonist) (pK₉ 7.9) [2273]

[³H]QNB (Antagonist) (pK₉ 10.1–10.6) [1683], Cy3B-telenzepine (Antagonist) (pKᵢ 10.4) [1568], [³H]tiotropium (Antagonist) (pK₉ 10.3) [1856], [³H]N-methyl scopolamine (Antagonist) (pK₉ 9.3–9.9) [324, 358, 878, 976, 977, 1011, 1074, 1212, 2261], Alexa-488-telenzepine (Antagonist) (pKᵢ 8.8) [1568], [³H]acetylcholine (Agonist) [1213], [³H]oxotremorine-M (Agonist) [153], [³H]dimethyl-W84 (Allosteric modulator, Positive) (pK₉ 8.5) [2154], [¹⁸F]FP-TZTP (Agonist) [975] – Mouse
<table><thead><tr><th></th><th>M3 receptor</th><th>M4 receptor</th><th>M5 receptor</th></tr></thead><tbody><tr><td>Nomenclature</td><td>M3 receptor</td><td>M4 receptor</td><td>M5 receptor</td></tr><tr><td>HGNC, UniProt</td><td>CHRM3, P20309</td><td>CHRM4, P08173</td><td>CHRMS, P08912</td></tr><tr><td>Agonists</td><td>pilocarpine (Partial agonist) [976], carbachol [358, 976, 2326], bethanechol [976]</td><td>pilocarpine (Partial agonist) [976], carbachol [976, 2326], bethanechol [976]</td><td>pilocarpine (Partial agonist) [740], carbachol [2326]</td></tr><tr><td>Antagonists</td><td>tiotropium (pK<sub>i</sub> 9.5–11.1) [501, 519], AE9C90CB (pK<sub>i</sub> 9.9) [1979], atropine (pK<sub>i</sub> 8.9–9.8) [265, 519, 878, 923, 1683, 1993], ipratropium (pK<sub>i</sub> 9.3–9.8) [519, 878], acclidinium (pIC<sub>50</sub> 9.8) [1733]</td><td>glycopyrrolate (pIC<sub>50</sub> 9.8) [2037], AE9C90CB (pK<sub>i</sub> 9.5) [1979], 4-DAMP (pK<sub>i</sub> 8.9) [537], oxybutynin (pK<sub>i</sub> 8.7) [1979], biperiden (pK<sub>d</sub> 8.6) [190], UH-AH 37 (pK<sub>i</sub> 8.3–8.4) [704, 2292]</td><td>glycopyrrolate (pIC<sub>50</sub> 9.7) [2037], AE9C90CB (pK<sub>i</sub> 9.5) [1979], 4-DAMP (pK<sub>i</sub> 9) [537], tolterodine (pK<sub>i</sub> 8.5–8.8) [704, 1979], darifenacin (pK<sub>i</sub> 7.9–8.6) [704, 841, 878, 1979]</td></tr><tr><td>Selective antagonists</td><td>–</td><td>–</td><td>ML381 (pK<sub>i</sub> 6.3) [684]</td></tr><tr><td>Allosteric modulators</td><td>WIN 62,577 (Positive) (pK<sub>d</sub> 5.1) [1216], N-chloromethyl-brucine (Positive) (pK<sub>d</sub> 3.3) [1214]</td><td>muscarinic toxin 3 (Negative) (pK<sub>i</sub> 8.7) [1011, 1635], VU0152100 (Positive) (pEC<sub>50</sub> 6.4) [224] – Rat, VU0152099 (Positive) (pEC<sub>50</sub> 6.4) [224] – Rat, LY2119620 (Positive) (pK<sub>d</sub> 5.7) [437], thiochrome (Positive) (pK<sub>d</sub> 4) [1213], LY2033298 (Positive) [333]</td><td>ML380 (Positive) (pEC<sub>50</sub> 6.7) [149, 686]</td></tr><tr><td>Selective allosteric modulators</td><td>–</td><td>–</td><td>ML375 (Negative) (pIC<sub>50</sub> 6.5) [685]</td></tr><tr><td>Labelled ligands</td><td>[<sup>3</sup>H]tiotropium (Antagonist) (pK<sub>d</sub> 10.7) [1856], [<sup>3</sup>H]QNB (Antagonist) (pK<sub>d</sub> 10.4) [1683], [<sup>3</sup>H]N-methyl scopolamine (Antagonist) (pK<sub>d</sub> 9.7–10.2) [324, 358, 878, 923, 976, 1011, 1074, 1212], [<sup>3</sup>H]darifenacin (Antagonist) (pK<sub>d</sub> 9.5) [1993]</td><td>[<sup>3</sup>H]QNB (Antagonist) (pK<sub>d</sub> 9.7–10.5) [387, 1683], [<sup>3</sup>H]N-methyl scopolamine (Antagonist) (pK<sub>d</sub> 9.9–10.2) [324, 358, 387, 878, 976, 1011, 1074, 1212, 1635, 2261], [<sup>3</sup>H]acetylcholine (Agonist) [1213]</td><td>[<sup>3</sup>H]QNB (Antagonist) (pK<sub>d</sub> 10.2–10.7), [<sup>3</sup>H]N-methyl scopolamine (Antagonist) (pK<sub>d</sub> 9.3–9.7) [324, 358, 878, 1011, 1074, 2261]</td></tr></tbody></table>

**Comments:** The crystal structures of the M₁-M₄ receptor subtypes have been reported [777, 2111, 2382]. Direct activation via an allosteric site has been reported for M₁ receptors (BQCA, PF-06767832) and M₄ receptors (LY2033298) [462, 1225, 1227, 1336, 1550, 1551]. The allosteric site for gallamine and strychnine on M₂ receptors can be labelled by [<sup>3</sup>H]dimethyl-W84 [2155]. McN-A-343 is a functionally selective partial agonist that appears

to interact in a bitopic mode with both the orthosteric and an allosteric site on the M₂ muscarinic receptor [2186]. THRX160209, hybrid 1 and hybrid 2, are multivalent (bitopic) ligands that also achieve selectivity for M₂ receptors by binding both to the orthosteric and a nearby allosteric site [59, 2028].

Although numerous ligands for muscarinic acetylcholine receptors have been described, relatively few selective antagonists have

been described, so it is common to assess the rank order of affinity of a number of antagonists of limited selectivity (e.g. 4-DAMP, darifenacin, pirenzepine) in order to identify the involvement of particular subtypes. It should be noted that the measured affinities of antagonists (and agonists) in radioligand binding studies are sensitive to ionic strength and can increase over 10-fold at low ionic strength compared to their values at physiological ionic strengths [167].

## Further reading on Acetylcholine receptors (muscarinic)

* Burger WAC et al. (2018) Toward an understanding of the structural basis of allostery in muscarinic acetylcholine receptors. *J Gen Physiol* **150**: 1360-1372 [PMID:30190312]

* Caulfield MP et al. (1998) International Union of Pharmacology. XVII. Classification of muscarinic acetylcholine receptors. *Pharmacol Rev* **50**: 279-290 [PMID:9647869]

* Eglen RM. (2012) Overview of muscarinic receptor subtypes. *Handb Exp Pharmacol* 3-28 [PMID:22222692]

* Kruse AC et al. (2014) Muscarinic acetylcholine receptors: novel opportunities for drug development. *Nat Rev Drug Discov* **13**: 549-60 [PMID:24903776]

* Leach K et al. (2012) Structure-function studies of muscarinic acetylcholine receptors. *Handb Exp Pharmacol* 29-48 [PMID:22222693]

* Valant C et al. (2012) The best of both worlds? Bitopic orthosteric/allosteric ligands of g protein-coupled receptors. *Annu Rev Pharmacol Toxicol* **52**: 153-78 [PMID:21910627]
# Adenosine receptors

G protein-coupled receptors → Adenosine receptors

**Overview:** Adenosine receptors (nomenclature as agreed by the NC-IUPHAR Subcommittee on Adenosine Receptors [624]) are activated by the endogenous ligand adenosine (potentially inosine also at A₃ receptors). Crystal structures for the

antagonist-bound [410, 964, 1307, 1922], agonist-bound [1232, 1233, 2354] and G protein-bound A₂A adenosine receptors [307] have been described. The structures of an antagonist-bound A1 receptor [712] and an adenosine-bound A1 receptor-Gᵢ complex

[521] have been resolved by cryo-electronmicroscopy. Another structure of an antagonist-bound A1 receptor obtained with X-ray crystallography has also been reported [361].

<table><thead><tr><th></th><th></th><th></th><th></th><th></th></tr></thead><tbody><tr><td>Nomenclature</td><td>A₁ receptor</td><td>A₂A receptor</td><td>A₂B receptor</td><td>A₃ receptor</td></tr><tr><td>HGNC, UniProt</td><td>ADORA1, P30542</td><td>ADORA2A, P29274</td><td>ADORA2B, P29275</td><td>ADORA3, P0DMS8</td></tr><tr><td>Endogenous agonists</td><td>adenosine [2369]</td><td>adenosine [2369]</td><td>adenosine [2369]</td><td>adenosine [2369]</td></tr><tr><td>Agonists</td><td>NECA [658, 1005, 1813, 2151, 2369]</td><td>NECA [209, 500, 658, 1088, 1173, 2369]</td><td>NECA [160, 209, 995, 1289, 2033, 2203, 2369]</td><td>NECA [209, 658, 971, 1858, 2204, 2369]</td></tr><tr><td>Selective agonists</td><td>cyclopentyladenosine [442, 469, 658, 848, 968, 1005, 1813], S-Cl-5-deoxy-(±)-ENBA [620], TCPA [162], CCPA [968, 1609], MRS7469 [2148]</td><td>apadenoson [1674], UK-432,097 [768, 2354], AZD4635 [410], CGS 21680 [209, 500, 658, 968, 1088, 1115, 1173, 1609], regadenoson [968]</td><td>BAY 60-6583 [539]</td><td>piclidenoson [592, 647, 1115, 2204], CI-IB-MECA [225, 971, 1085], MRS5698 [2147]</td></tr><tr><td>Antagonists</td><td>CGS 15943 (pKᵢ 8.5) [1636], xanthine amine congener (pK₉ 7.5) [620]</td><td>CGS 15943 (pKᵢ 7.7–9.4) [500, 1088, 1115, 1636], xanthine amine congener (pKᵢ 8.4–9) [500, 1115]</td><td>xanthine amine congener (pKᵢ 6.9–8.8) [160, 995, 996, 1115, 1289, 2033], CGS 15943 (pKᵢ 6–8.1) [76, 995, 996, 1115, 1636, 2033]</td><td>CGS 15943 (pKᵢ 7–7.9) [1093, 1115, 1636, 2204], xanthine amine congener (pKᵢ 7–7.4) [1115, 1858, 2204]</td></tr><tr><td>Selective antagonists</td><td>PSB36 (pKᵢ 9.9) [6] – Rat, DPCPX (pKᵢ 7.4–9.2) [469, 950, 1609, 1813, 2295], derenofylline (pKᵢ 9) [1033], WRC-0571 (pKᵢ 8.8) [1387], DU172 (pKᵢ 7.4) [712]</td><td>SCH442416 (pKᵢ 8.4–10.3) [1957, 2139], ZM-241385 (pKᵢ 8.8–9.1) [1636]</td><td>PSB-0788 (pKᵢ 9.4) [208], PSB603 (pKᵢ 9.3) [208], MRS1754 (pKᵢ 8.8) [995, 1092], PSB1115 (pKᵢ 7.3) [832]</td><td>MRS1220 (pKᵢ 8.2–9.2) [971, 1093, 2055, 2384], VUF5574 (pKᵢ 8.4) [2193], MRS1523 (pKᵢ 7.7) [1268], MRS1191 (pKᵢ 7.5) [971, 998, 1273]</td></tr><tr><td>Allosteric modulators</td><td>PD81723 (Positive) [258]</td><td>–</td><td>–</td><td>LUF6000 (Positive) [772], LUF6096 (Positive) [847]</td></tr><tr><td>Labelled ligands</td><td>[³H]CCPA (Agonist) [1115, 1813], [³H]DPCPX (Antagonist) (pK₉ 8.4–9.2) [442, 592, 1115, 1636, 1813, 2151]</td><td>[³H]ZM 241385 (Antagonist) (pK₉ 8.7–9.1) [39, 656], [³H]CGS 21680 (Agonist) [983, 2246]</td><td>[³H]MRS1754 (Antagonist) (pK₉ 9.8) [995]</td><td>[¹²⁵I]AB-MECA (Agonist) [1636, 2204]</td></tr></tbody></table>

**Comments:** Adenosine inhibits many intracellular ATP-utilising enzymes, including adenylyl cyclase (P-site). A pseudogene exists for the A₂B adenosine receptor (ADORA2BP1) with 79% identity to the A₂B adenosine receptor cDNA coding sequence, but which is unable to encode a functional receptor [972]. DPCPX also exhibits antagonism at A₂B receptors (pKᵢ ca. 7, [37, 1115]).

Antagonists at A₃ receptors exhibit marked species differences, such that only MRS1523 and MRS1191 are selective at the rat A₃ receptor. In the absence of other adenosine receptors, [³H]DPCPX and [³H]ZM 241385 can also be used to label A₂B receptors (Kₚ ca. 30 and 60 nM respectively). [¹²⁵I]AB-MECA also binds to A₁ receptors [1115]. [³H]CGS 21680 is relatively selective for A₂A receptors,

but may also bind to other sites in cerebral cortex [438, 1006]. [³H]NECA binds to other non-receptor elements, which also recognise adenosine [1318]. XAC-BY630 has been described as a fluorescent antagonist for labelling A₁ adenosine receptors in living cells, although activity at other adenosine receptors was not examined [234].
Further reading on Adenosine receptors

Borea PA *et al.* (2015) The A3 adenosine receptor: history and perspectives. *Pharmacol Rev* **67**: 74-102 [PMID:25387804]

Cronstein BN *et al.* (2017) Adenosine and adenosine receptors in the pathogenesis and treatment of rheumatic diseases. *Nat Rev Rheumatol* **13**: 41-51 [PMID:27829671]

Fredholm BB *et al.* (2011) International Union of Basic and Clinical Pharmacology. LXXXI. Nomenclature and classification of adenosine receptors–an update. *Pharmacol Rev* **63**: 1-34 [PMID:21303899]

Guo D *et al.* (2017) Kinetic Aspects of the Interaction between Ligand and G Protein-Coupled Receptor: The Case of the Adenosine Receptors. *Chem Rev* **117**: 38-66 [PMID:27088232]

Göblyös A *et al.* (2011) Allosteric modulation of adenosine receptors. *Biochim Biophys Acta* **1808**: 1309-18 [PMID:20599682]

Lasley RD. (2011) Adenosine receptors and membrane microdomains. *Biochim Biophys Acta* **1808**: 1284-9 [PMID:20888790]

Mundell S *et al.* (2011) Adenosine receptor desensitization and trafficking. *Biochim Biophys Acta* **1808**: 1319-28 [PMID:20550943]

Vecchio EA *et al.* (2018) New paradigms in adenosine receptor pharmacology: allostery, oligomerization and biased agonism. *Br J Pharmacol* **175**: 4036-4046 [PMID:29679502]

Wei CJ *et al.* (2011) Normal and abnormal functions of adenosine receptors in the central nervous system revealed by genetic knockout studies. *Biochim Biophys Acta* **1808**: 1358-79 [PMID:21185258]

Adhesion Class GPCRs

G protein-coupled receptors → Adhesion Class GPCRs

**Overview:** Adhesion GPCRs are structurally identified on the basis of a large extracellular region, similar to the Class B GPCR, but which is linked to the 7TM region by a GPCR autoproteolysis-inducing (GAIN) domain [60] containing a GPCR proteolytic

site. The N-terminus often shares structural homology with adhesive domains (e.g. cadherins, immunolobulin, lectins) facilitating inter- and matricellular interactions and leading to the term adhesion GPCR [626, 2397].

Several receptors have been suggested to function as mechanosensors [219, 1697, 1900, 2310]. **The nomenclature of these receptors was revised in 2015 as recommended by NC-IUPHAR and the Adhesion GPCR Consortium** [788].

<table><tr><td>Nomenclature</td><td>ADGRA1</td><td>ADGRA2</td><td>ADGRA3</td><td>ADGRB1</td><td>ADGRB2</td><td>ADGRB3</td></tr><tr><td>HGNC, UniProt</td><td>ADGRA1, Q86SQ6</td><td>ADGRA2, Q96PE1</td><td>ADGRA3, Q8IWK6</td><td>ADGRB1, O14514<br>phosphatidylserine<br>[1655]</td><td>ADGRB2, O60241</td><td>ADGRB3, O60242</td></tr><tr><td>Endogenous agonists</td><td>—</td><td>—</td><td>—</td><td>—</td><td>—</td><td>—</td></tr><tr><td>Comments</td><td>—</td><td>Required to assemble<br>higher-order<br>Reck/Gpr124/Frizzled/<br>Lrp5/6 complexes [573,<br>1726, 2188, 2200, 2436].</td><td>—</td><td>Reported to mediate<br>phagocytosis through<br>binding of<br>phosphatidylserine<br>[1655] and<br>lipopolysaccharide [447].</td><td>—</td><td>Reported to bind C1q-like molecules [194].</td></tr></table>
<table><tr><td>Nomenclature</td><td>CELSR1</td><td>CELSR2</td><td>CELSR3</td><td>ADGRD1</td><td>ADGRD2</td></tr><tr><td>HGNC, UniProt</td><td>CELSR1, Q9NYQ6</td><td>CELSR2, Q9HCU4</td><td>CELSR3, Q9NYQ7</td><td>ADGRD1, Q6QNK2</td><td>ADGRD2, Q7Z7M1</td></tr><tr><td>Comments</td><td>–</td><td>Mutated in Joubert syndrome patients [2218].</td><td>High-confidence risk gene for Tourette syndrome [2260].</td><td>Is a G<sub>s</sub> protein-coupled receptor [186, 1278] and highly expressed in glioblastoma [122].</td><td>–</td></tr></table>

<table><tr><td>Nomenclature</td><td>ADGRE1</td><td>ADGRE2</td><td>ADGRE3</td><td>ADGRE4P</td><td>ADGRE5</td></tr><tr><td>HGNC, UniProt</td><td>ADGRE1, Q14246</td><td>ADGRE2, Q9UHX3</td><td>ADGRE3, Q9BY15</td><td>ADGRE4P, Q86SQ3</td><td>ADGRE5, P48960</td></tr><tr><td>Comments</td><td>–</td><td>A mutation destabilizing the GAIN domain sensitizes mast cells to IgE-independent vibration-induced degranulation [219]. Reported to bind chondroitin sulfate B [2024].</td><td>–</td><td>–</td><td>Reported to bind CD55 [789], chondroitin sulfate B [2024], α<sub>5</sub>β<sub>1</sub> and α<sub>γ</sub>β<sub>3</sub> integrins [2262], and CD90 [2248].</td></tr></table>

<table><tr><td>Nomenclature</td><td>ADGRF1</td><td>ADGRF2</td><td>ADGRF3</td><td>ADGRF4</td><td>ADGRF5</td></tr><tr><td>HGNC, UniProt</td><td>ADGRF1, Q5T601</td><td>ADGRF2, Q8IZF7</td><td>ADGRF3, Q8IZF5</td><td>ADGRF4, Q8IZF3</td><td>ADGRF5, Q8IZF2</td></tr><tr><td>Comments</td><td>Synaptamide is an agonist at ADGRF1 supporting neurogenesis [1240] and couples to G<sub>s</sub> and G<sub>q</sub> pathways [482, 2041].</td><td>ADGRF2 is highly expressed in squamous epithelia and gene deficiency did not result in detectable defects [1744].</td><td>ADGRF3 is highly expressed in gastrointestinal neuroendocrine tumors [308, 308].</td><td>ADGRF4 couples to G<sub>q</sub>/11 proteins [482], is highly expressed in squamous epithelia and gene deficiency did not result in detectable defects [1744].</td><td>ADGRF5 controls alveolar surfactant secretion via G<sub>q</sub>/11 pathway [253].</td></tr></table>

<table><tr><td>Nomenclature</td><td>ADGRG1</td><td>ADGRG2</td><td>ADGRG3</td><td>ADGRG4</td><td>ADGRG5</td><td>ADGRG6</td><td>ADGRG7</td></tr><tr><td>HGNC, UniProt</td><td>ADGRG1, Q9Y653</td><td>ADGRG2, Q8IZP9</td><td>ADGRG3, Q86Y34</td><td>ADGRG4, Q8IZF6</td><td>ADGRG5, Q8IZF4</td><td>ADGRG6, Q86SQ4</td><td>ADGRG7, Q96K78</td></tr><tr><td>Comments</td><td>Reported to bind tissue transglutaminase 2 [2355] and collagen, which activates the G<sub>12/13</sub> pathway [1330].</td><td>ADGRG2 is coupled to G<sub>q</sub> and G<sub>s</sub> pathways [481] and gene deficiency causes congenital obstructive azoospermia [1663].</td><td>ADGRG3 is expressed in immune cells [1947, 2255] and couples to G<sub>o</sub> proteins [770].</td><td>ADGRG4 is highly expressed in enterochromaffin cells and gastrointestinal neuroendocrine tumors [1250].</td><td>ADGRG5 is a constitutively active G<sub>s</sub> protein-coupled receptor [770, 2310], highly expressed in eosinophils and NK cells [1682].</td><td>ADGRG6 is a key regulator of Schwann cell-mediated myelination [1481], and couples to G<sub>s</sub> and G<sub>i/o</sub> pathways [1468].</td><td>ADGRG7 is expressed in interstine and involved in interstine contractility regulation [1580].</td></tr></table>
Nomenclature
HGNC, UniProt

Comments

ADGRL1
ADGRL1, O94910

Couples to Gs and Gq pathways
[1252, 1533].

ADGRL2
ADGRL2, O95490

-

ADGRL3
ADGRL3, Q9HAR2

A LPHN3 gene variant in humans is
associated with
attention-deficit-hyperactivity
disorder [62, 2313].

ADGRL4
ADGRL4, Q9HBW9

-

ADGRV1
ADGRV1, Q8WXG9

Loss-of-function mutations are
associated with Usher syndrome, a
sensory deficit disorder [973].

Further reading on Adhesion Class GPCRs

Hamann J et al. (2015) International Union of Basic and Clinical Pharmacology. XCIV. Adhesion G protein-coupled receptors. *Pharmacol Rev* **67**: 338-67 [PMID:25713288]

Langenhan T et al. (2013) Sticky signaling–adhesion class G protein-coupled receptors take the stage. *Sci Signal* **6**: re3 [PMID:23695165]

Liebscher I et al. (2016) Tethered Agonism: A Common Activation Mechanism of Adhesion GPCRs. *Handb Exp Pharmacol* **234**: 111-125 [PMID:27832486]

Monk KR et al. (2015) Adhesion G Protein-Coupled Receptors: From In Vitro Pharmacology to In Vivo Mechanisms. *Mol Pharmacol* **88**: 617-23 [PMID:25956432]

Purcell RH et al. (2018) Adhesion G Protein-Coupled Receptors as Drug Targets. *Annu Rev Pharmacol Toxicol* **58**: 429-449 [PMID:28968187]
# Adrenoceptors

G protein-coupled receptors → Adrenoceptors

**Overview:** The nomenclature of the Adrenoceptors has been agreed by the **NC-IUPHAR** Subcommittee on Adrenoceptors [277], see also [869].

## Adrenoceptors, α₁

α₁-Adrenoceptors are activated by the endogenous agonists (-)-adrenaline and (-)-noradrenaline. Phenylephrine, methoxamine and cirazoline are agonists and prazosin and cirazoline antagonists considered selective for α₁- relative to α₂-adrenoceptors. [³H]prazosin and [¹²⁵I]HEAT (BE2254) are

relatively selective radioligands. S(+)-niguldipine also has high affinity for L-type Ca²⁺ channels. Fluorescent derivatives of prazosin (Bodipy PLprazosin- QAPB) are used to examine cellular localisation of α₁-adrenoceptors. Selective α₁-adrenoceptor agonists are used as nasal decongestants; antagonists to treat hypertension (doxazosin, prazosin) and benign prostatic hyperplasia

(alfuzosin, tamsulosin). The α₁- and β₂-adrenoceptor antagonist carvedilol is used to treat congestive heart failure, although the contribution of α₁-adrenoceptor blockade to the therapeutic effect is unclear. Several anti-depressants and anti-psychotic drugs are α₁-adrenoceptor antagonists contributing to side effects such as orthostatic hypotension and extrapyramidal effects.

<table><tr><td>Nomenclature</td><td>α₁A-adrenoceptor</td><td>α₁B-adrenoceptor</td><td>α₁D-adrenoceptor</td></tr><tr><td>HGNC, UniProt</td><td>ADRA1A, P35348</td><td>ADRA1B, P35368</td><td>ADRA1D, P25100</td></tr><tr><td>Endogenous agonists</td><td>(-)-adrenaline [904, 1948], (-)-noradrenaline [904, 1948, 2104]</td><td>–</td><td>(-)-noradrenaline [904, 1948], (-)-adrenaline [904, 1948]</td></tr><tr><td>Agonists</td><td>oxymetazoline [904, 1610, 1948, 2104], phenylephrine [2104], methoxamine [1948, 2104]</td><td>phenylephrine [614, 1459]</td><td>–</td></tr><tr><td>Selective agonists</td><td>A61603 [614, 1116], dabuzalgron [179]</td><td>–</td><td>–</td></tr><tr><td>Antagonists</td><td>prazosin (Inverse agonist) (pKᵢ 9.6–9.9) [335, 443, 614, 1948, 2312], doxazosin (pKᵢ 9.3) [795], terazosin (pKᵢ 8.7) [1436], phentolamine (pKᵢ 8.6) [1948], alfuzosin (pKᵢ 8.1) [867]</td><td>prazosin (Inverse agonist) (pKᵢ 9.6–9.9) [614, 1948, 2312], tamsulosin (Inverse agonist) (pKᵢ 9.5–9.7) [614, 1948, 2312], doxazosin (pKᵢ 9.1) [795], alfuzosin (pKᵢ 8.6) [868], terazosin (pKᵢ 8.6) [1436], phentolamine (pKᵢ 7.5) [1948]</td><td>prazosin (Inverse agonist) (pKᵢ 9.5–10.2) [614, 1948, 2312], tamsulosin (pKᵢ 9.8–10.2) [614, 1948, 2312], doxazosin (pKᵢ 9.1) [795], terazosin (pKᵢ 9.1) [1436], alfuzosin (pKᵢ 8.4) [867], dapiprazole (pKᵢ 8.4) [79], phentolamine (Inverse agonist) (pKᵢ 8.2) [1948], RS-100329 (pKᵢ 7.9) [2312], labetalol (pKᵢ 6.6) [79]</td></tr><tr><td>Selective antagonists</td><td>tamsulosin (pKᵢ 10–10.7) [335, 443, 614, 1948, 2312], silodosin (pKᵢ 10.4) [1948], S(+)-niguldipine (pKᵢ 9.1–10) [614, 1948], RS-100329 (pKᵢ 9.6) [2312], SNAP5089 (pKᵢ 8.8–9.4) [867, 1256, 2294], ρ-Da1a (pKᵢ 9.2–9.3) [1412, 1755], RS-17053 (pKᵢ 9.2–9.3) [335, 443, 611, 614]</td><td>Rec 15/2615 (pKᵢ 9.5) [2110], L-765314 (pKᵢ 7.7) [1662], AH 11110 (pKᵢ 7.5) [1875]</td><td>BMY-7378 (pKᵢ 8.7–9.1) [310, 2403]</td></tr></table>

**Comments:** The α₁C-adrenoceptor corresponds to the pharmacologically defined α₁A-adrenoceptor [869]. Some tissues possess α₁A-adrenoceptors (α₁L-adrenoceptors [614, 1501]) that display relatively low affinity in functional and binding assays for prazosin indicative of different receptor states or locations. α₁A-adrenoceptor C-terminal splice variants form homo- and heterodimers, but fail to generate a functional α₁L-adrenoceptor

[1768]. α₁D-Adrenoceptors form heterodimers with α₁B- or β₂-adrenoceptors that show increased cell-surface expression [2164]. Recombinant α₁D-adrenoceptors have been shown in some heterologous systems to be mainly located intracellularly but cell-surface localization is encouraged by truncation of the N-terminus, or by co-expression of α₁B- or β₂-adrenoceptors [779, 2164]. In blood vessels all three α₁A-adrenoceptor subtypes are located on the surface and intracellularly [1433, 1434]. Signalling is

predominantly via Gq/11 but α₁A-adrenoceptors also couple to Gi/o, Gs and G12/13. Several α₁A-adrenoceptor agonists display ligand directed signalling bias relative to noradrenaline [575]. There are also differences between subtypes in coupling efficiency to different pathways. In vascular smooth muscle, the potency of agonists is related to the predominant subtype, α₁D- conveying greater agonist sensitivity than α₁A-adrenoceptors [609].
## Adrenoceptors, α₂

α₂-Adrenoceptors are activated by (-)-adrenaline and with lower potency by (-)-noradrenaline. Brimonidine and talipecox are agonists and rauwolscine and yohimbine antagonists selective for α₂- relative to α₁-adrenoceptors. [³H]rauwolscine, [³H]brimonidine and [³H]RX821002 are relatively selective radioligands. There is species variation in the pharmacology of

the α₂A-adrenoceptor. Multiple mutations of α₂-adrenoceptors have been described, some associated with alterations in function. Presynaptic α₂-adrenoceptors regulate many functions in the nervous system. The α₂-adrenoceptor agonists clonidine, guanabenz and brimonidine affect central baroreflex control (hypotension and bradycardia), induce hypnotic effects and analgesia, and modulate seizure activity and platelet aggregation. Clonidine is an anti-hypertensive and counteracts opioid with-

drawal. Dexmedetomidine (also xylazine) is used as a sedative and analgesic in human and veterinary medicine with sympathetic and anxiolytic properties. The α₂-adrenoceptor antagonist yohimbine has been used to treat erectile dysfunction and mirtazapine as an anti-depressant. The α₂B subtype appears to be involved in neurotransmission in the spinal cord and α₂C in regulating catecholamine release from adrenal chromaffin cells.

<table><thead><tr><th></th><th></th><th></th><th></th></tr></thead><tbody><tr><td>Nomenclature</td><td>α₂A-adrenoceptor</td><td>α₂B-adrenoceptor</td><td>α₂C-adrenoceptor</td></tr><tr><td>HGNC, UniProt</td><td>ADRA2A, P08913</td><td>ADRA2B, P18089</td><td>ADRA2C, P18825</td></tr><tr><td>Endogenous agonists</td><td>(-)-adrenaline [985, 1704], (-)-noradrenaline [985, 1704]</td><td>(-)-noradrenaline (Partial agonist) [985, 1704], (-)-adrenaline [985]</td><td>(-)-noradrenaline [985, 1704], (-)-adrenaline [985]</td></tr><tr><td>Agonists</td><td>dexmedetomidine (Partial agonist) [985, 1339, 1678, 1704], clonidine (Partial agonist) [985, 1678, 1704], brimonidine [985, 1339, 1678, 1704], apraclonidine [1519], guanabenz [79], guanfacine (Partial agonist) [985, 1342]</td><td>dexmedetomidine [985, 1339, 1678, 1704], clonidine (Partial agonist) [985, 1678, 1704], brimonidine (Partial agonist) [985, 1678, 1704], guanabenz [79], guanfacine [985]</td><td>dexmedetomidine [985, 1678, 1704], brimonidine (Partial agonist) [985, 1339, 1678, 1704], apraclonidine [1519], guanfacine (Partial agonist) [985], guanabenz [79]</td></tr><tr><td>Selective agonists</td><td>oxymetazoline (Partial agonist) [985, 1339, 2169]</td><td>–</td><td>–</td></tr><tr><td>Antagonists</td><td>yohimbine (pK<sub>i</sub> 8.4–9.2) [276, 487, 2169]</td><td>yohimbine (pK<sub>i</sub> 7.9–8.9) [276, 487, 2169], phenoxybenzamine (pK<sub>i</sub> 8.5) [2280], tolazoline (pK<sub>i</sub> 5.5) [985]</td><td>yohimbine (pK<sub>i</sub> 8.5–9.5) [276, 487, 2169], WB 4101 (pK<sub>i</sub> 8.4–9.4) [276, 487, 2169], spiroxatrine (pK<sub>i</sub> 9) [2169], mirtazapine (pK<sub>i</sub> 7.7) [593], tolazoline (pK<sub>i</sub> 5.4) [985]</td></tr><tr><td>Selective antagonists</td><td>BRL 44408 (pK<sub>i</sub> 8.2–8.8) [2169, 2405]</td><td>imiloxan (pK<sub>i</sub> 7.3) [1443] – Rat</td><td>JP1302 (pK<sub>B</sub> 7.8) [1855]</td></tr><tr><td>Labelled ligands</td><td>–</td><td>–</td><td>[³H]MK-912 (Antagonist) (pK<sub>d</sub> 10.1) [2169]</td></tr></tbody></table>

**Comments:** ARC-239 and prazosin show selectivity for α₂B- and α₂C-adrenoceptors over α₂A-adrenoceptors. Oxymetazoline is a reduced efficacy imidazoline agonist but also binds to non-GPCR binding sites for imidazolines, classified as I₁, I₂ and I₃ sites [444]; catecholamines have a low affinity, while rilmenidine and moxonidine are selective ligands evoking hypotensive effects *in vivo*. I₁-imidazoline receptors cause central inhibition of sympathetic

tone, I₂-imidazoline receptors are an allosteric binding site on monoamine oxidase B, and I₃-imidazoline receptors regulate insulin secretion from pancreatic β-cells. α₂A-adrenoceptor stimulation reduces insulin secretion from β-islets [2375], with a polymorphism in the 5'-UTR of the ADRA2A gene being associated with increased receptor expression in β-islets and heightened susceptibility to diabetes [1821]. α₂A- and α₂C-adrenoceptors form homodimers [1990]. Heterodimers between α₂A- and either the

α₂C-adrenoceptor or μ opioid peptide receptor exhibit altered signalling and trafficking properties compared to the individual receptors [1990, 2099, 2217]. Signalling by α₂-adrenoceptors is primarily via Gᵢ/o, although the α₂A-adrenoceptor also couples to Gₛ [538]. Imidazoline compounds display bias relative to each other at the α₂A-adrenoceptor [1670]. The noradrenaline reuptake inhibitor desipramine acts directly on the α₂A-adrenoceptor to promote internalisation *via* recruitment of arrestin [421].

## Adrenoceptors, β

β-Adrenoceptors are activated by the endogenous agonists (-)-adrenaline and (-)-noradrenaline. Isoprenaline is selective for β-adrenoceptors relative to α₁- and α₂-adrenoceptors, while propranolol (pKᵢ 8.2-9.2) and cyanopindolol (pKᵢ 10.0-11.0) are relatively β₁ and β₂ adrenoceptor-selective antagonists. (-)-noradrenaline, xamoterol and (-)-Ro 363 show selectivity for β₁- relative to β₂-adrenoceptors. Pharmacological differences ex-

ist between human and mouse β₃-adrenoceptors, and the 'rodent selective' agonists BRL 37344 and CL316243 have low efficacy at the human β₃-adrenoceptor whereas CGP 12177 and L 755507 activate human β₃-adrenoceptors [88]. β₃-Adrenoceptors are resistant to blockade by propranolol, but can be blocked by high concentrations of bupropionol. SR59230A has reasonably high affinity at β₃-adrenoceptors, but does not discriminate well between the three β- subtypes whereas L 755507 is

more selective. [¹²⁵I]-cyanopindolol, [¹²⁵I]-hydroxy benzylpindolol and [³H]-alprenolol are high affinity radioligands that label β₁- and β₂- adrenoceptors and β₃-adrenoceptors can be labelled with higher concentrations (nM) of [¹²⁵I]-cyanopindolol together with β₁- and β₂-adrenoceptor antagonists. [³H]-L-748337 is a β₃-selective radioligand [2197]. Fluorescent ligands such as BODIPY-TMR-CGP12177 can be used to track β-adrenoceptors at the cellular level [8]. Somewhat selective β₁-
adrenoceptor agonists (denopamine, dobutamine) are used short term to treat cardiogenic shock but, chronically, reduce survival. β₁-Adrenoceptor-preferring antagonists are used to treat hypertension (atenolol, betaxolol, bisoprolol, metoprolol and nebivolol), cardiac arrhythmias (atenolol, bisoprolol, esmolol) and cardiac

failure (metoprolol, nebivolol). Cardiac failure is also treated with carvedilol that blocks β₁- and β₂-adrenoceptors, as well as α₁-adrenoceptors. Short (salbutamol, terbutaline) and long (formoterol, salmeterol) acting β₂-adrenoceptor-selective agonists are powerful bronchodilators used to treat respiratory disorders.

Many first generation β-adrenoceptor antagonists (propranolol) block both β₁- and β₂-adrenoceptors and there are no β₂-adrenoceptor-selective antagonists used therapeutically. The β₃-adrenoceptor agonist mirabegron is used to control overactive bladder syndrome.

<table><thead><tr><th></th><th>β₁-adrenoceptor</th><th>β₂-adrenoceptor</th><th>β₃-adrenoceptor</th></tr></thead><tbody><tr><td>Nomenclature</td><td>β₁-adrenoceptor</td><td>β₂-adrenoceptor</td><td>β₃-adrenoceptor</td></tr><tr><td>HGNC, UniProt</td><td>ADR81, P08588</td><td>ADR82, P07550</td><td>ADR83, P13945</td></tr><tr><td>Potency order of endogenous ligands</td><td>(-)-noradrenaline > (-)-adrenaline</td><td>(-)-adrenaline > (-)-noradrenaline</td><td>(-)-noradrenaline = (-)-adrenaline</td></tr><tr><td>Endogenous agonists</td><td>(-)-adrenaline [633, 891], (-)-noradrenaline [633, 891], noradrenaline [633]</td><td>(-)-adrenaline [633, 891, 982], (-)-noradrenaline [633, 891]</td><td>(-)-noradrenaline [891, 1720, 2044], (-)-adrenaline [891]</td></tr><tr><td>Agonists</td><td>pindolol (Partial agonist) [1159], isoprenaline [633, 1874], dobutamine (Partial agonist) [956]</td><td>pindolol (Partial agonist) [1159], arformoterol [40], isoprenaline [1874], ephedrine (Partial agonist) [982]</td><td>carazolol [1431]</td></tr><tr><td>Selective agonists</td><td>(-)-Ro 363 [1472], xamoterol (Partial agonist) [956], denopamine (Partial agonist) [956, 2066]</td><td>formoterol [94], salmeterol [94], zinterol [94], vilanterol [1737], procaterol [94], indacaterol [123], fenoterol [65], salbutamol (Partial agonist) [96, 956], terbutaline (Partial agonist) [96], orciprenaline [2014]</td><td>L 755507 [94], L742791 [2277], mirabegron [2089], CGP 12177 (Partial agonist) [177, 1319, 1431, 1472], SB251023 [936] – Mouse, BRL 37344 [177, 505, 891, 1431], CL316243 [2372]</td></tr><tr><td>Antagonists</td><td>carvedilol (pKᵢ 9.5) [297], bupranolol (pKᵢ 7.3–9) [297, 1319], SR59230A (pKᵢ 8.6) [297], levobunolol (pKᵢ 8.4) [79], labetalol (pKᵢ 8.2) [79], metoprolol (pKᵢ 7–7.6) [96, 297, 891, 1319], esmolol (pKᵢ 6.9) [79], nadolol (pKᵢ 6.9) [297], practolol (pKᵢ 6.1–6.8) [96, 1319], propafenone (pKᵢ 6.7) [79], sotalol (pKᵢ 6.1) [79]</td><td>carvedilol (pKᵢ 9.4–9.9) [96, 297], timolol (pKᵢ 9.7) [96], propranolol (pKᵢ 9.1–9.5) [96, 99, 956, 1319], SR59230A (pKᵢ 9.3) [297], levobunolol (pKᵢ 9.3) [79], bupranolol (pKᵢ 8.3–9.1) [297, 1319], alprenolol (pKᵢ 9) [96], nadolol (pKᵢ 7–8.6) [96, 297], labetalol (pKᵢ 8) [79], propafenone (pKᵢ 7.4) [79], sotalol (pKᵢ 6.5) [79]</td><td>SR59230A (pKᵢ 6.9–8.4) [297, 471, 891], bupranolol (pKᵢ 6.8–7.3) [177, 297, 1319, 1431], propranolol (pKᵢ 6.3–7.2) [1319, 1720], levobunolol (pKᵢ 6.8) [1720]</td></tr><tr><td>Selective antagonists</td><td>CGP 20712A (pKᵢ 8.5–9.2) [96, 297, 1319], levobetaxolol (pKᵢ 9.1) [1942], betaxolol (pKᵢ 8.8) [1319], nebivolol (pIC₅₀ 8.1–8.7) [1669] – Rabbit, atenolol (pKᵢ 6.7–7.6) [96, 1021, 1319], acebutolol (pKᵢ 6.4) [79]</td><td>ICI 118551 (Inverse agonist) (pKᵢ 9.2–9.5) [96, 99, 1319]</td><td>L-748337 (pKᵢ 8.4) [297], L748328 (pKᵢ 8.4) [297]</td></tr><tr><td>Labelled ligands</td><td>[125I]ICYP (Antagonist) (pK₉ 10.4–11.3) [956, 1319, 1874]</td><td>[125I]ICYP (Antagonist) (pK₉ 11.1) [1319, 1874]</td><td>[125I]ICYP (Agonist, Partial agonist) [1319, 1472, 1720, 1874, 2044]</td></tr><tr><td>Comments</td><td>The agonists indicated have less than two orders of magnitude selectivity [94].</td><td>–</td><td>Agonist SB251023 has a pEC₅₀ of 6.9 for the splice variant of the mouse β₃ receptor, β₃b [936].</td></tr></tbody></table>

**Comments:** [125I]ICYP can be used to define β₁- or β₂-adrenoceptors when conducted in the presence of a β₁- or β₂-adrenoceptor-selective antagonist. A fluorescent analogue of CGP 12177 can be used to study β₂-adrenoceptors in living cells [97]. [125I]ICYP at higher (nM) concentrations can be used to label β₃-adrenoceptors in systems with few if any other β-adrenoceptor subtypes. The β₃-adrenoceptor has an intron in the coding region, but splice variants have only been described for the mouse [576], where the isoforms display different signalling characteristics

[936]. There are 3 β-adrenoceptors in turkey (termed the tβ, tβ3c and tβ4c) that have a pharmacology that differs from the human β-adrenoceptors [95]. Numerous polymorphisms have been described for the β-adrenoceptors; some are associated with signalling and trafficking, altered susceptibility to disease and/or altered responses to pharmacotherapy [1279]. All β-adrenoceptors couple to Gs (activating adenylyl cyclase and elevating cAMP levels), but also activate Gi and β-arrestin-mediated signalling. Many β₁- and β₂-adrenoceptor antagonists are agonists at β₃-

adrenoceptors (CL316243, CGP 12177 and carazolol). Many ‘antagonists’ of cAMP accumulation, for example carvedilol and bucindolol, weakly activate MAP kinase pathways [98, 577, 644, 645, 1872, 1873] and thus display ‘protean agonism’. Bupranolol acts as a neutral antagonist in most systems so far examined. Agonists also display biased signalling at the β₂-adrenoceptor via Gs or arrestins [520]. X-ray crystal structures have been described of the agonist bound [2265] and antagonist bound forms of the β₁-[2266], agonist-bound [363] and antagonist-bound forms of the
β₂-adrenoceptor [1773, 1820], as well as a fully active agonist-bound, Gs protein-coupled β₂-adrenoceptor [1774]. Carvedilol and bucindolol bind to a site on the β₁-adrenoceptor involving contacts in TM2, 3, and 7 and extracellular loop 2 that may facilitate coupling to arrestins [2266]. Compounds displaying arrestin-

biased signalling at the β₂-adrenoceptor have a greater effect on the conformation of TM7, whereas full agonists for Gs coupling promote movement of TM5 and TM6 [1302]. Recent studies using NMR spectroscopy demonstrate significant conformational flexibility in the β₂-adrenoceptor that is stabilized by both agonist

and G proteins highlighting the dynamic nature of interactions with both ligand and downstream signalling partners [1090, 1372, 1605]. Such flexibility likely has consequences for our understanding of biased agonism, and for the future therapeutic exploitation of this phenomenon.

## Further reading on Adrenoceptors

* Baker JG et al. (2011) Evolution of β-blockers: from anti-anginal drugs to ligand-directed signalling. *Trends Pharmacol. Sci.* **32**: 227-34 [PMID:21429598]

* Bylund DB et al. (1994) International Union of Pharmacology nomenclature of adrenoceptors. *Pharmacol. Rev.* **46**: 121-136 [PMID:7938162]

* Evans BA et al. (2010) Ligand-directed signalling at beta-adrenoceptors. *Br. J. Pharmacol.* **159**: 1022-38 [PMID:20132209]

* Jensen BC et al. (2011) Alpha-1-adrenergic receptors: targets for agonist drugs to treat heart failure. *J. Mol. Cell. Cardiol.* **51**: 518-28 [PMID:21118696]

* Kobilka BK. (2011) Structural insights into adrenergic receptor function and pharmacology. *Trends Pharmacol. Sci.* **32**: 213-8 [PMID:21414670]

* Langer SZ. (2015) α2-Adrenoceptors in the treatment of major neuropsychiatric disorders. *Trends Pharmacol. Sci.* **36**: 196-202 [PMID:25771972]

* Michel MC et al. (2015) Selectivity of pharmacological tools: implications for use in cell physiology. A review in the theme: Cell signaling: proteins, pathways and mechanisms. *Am. J. Physiol., Cell Physiol.* **308**: C505-20 [PMID:25631871]

# Angiotensin receptors

G protein-coupled receptors → Angiotensin receptors

**Overview:** The actions of angiotensin II (AGT, P01019) (Ang II) are mediated by AT₁ and AT₂ receptors (nomenclature as agreed by the **NC-IUPHAR Subcommittee on Angiotensin receptors [465, 1045]**), which have around 30% sequence similarity. The decapeptide angiotensin I (AGT, P01019), the octapeptide angiotensin II (AGT, P01019) and the heptapeptide angiotensin III (AGT, P01019) are endogenous ligands. Losartan, candesartan, telmisartan, etc. are clinically used AT₁ receptor blockers.

<table><tr><td>Nomenclature</td><td>AT₁ receptor</td><td>AT₂ receptor</td></tr><tr><td>HGNC, UniProt</td><td>AGTR1, P30556</td><td>AGTR2, P50052</td></tr><tr><td>Endogenous agonists</td><td>angiotensin II (AGT, P01019) [466, 2199], angiotensin III (AGT, P01019) [466], angiotensin IV (AGT, P01019) (Partial agonist) [2122]</td><td>angiotensin III (AGT, P01019) [432, 466, 2298], angiotensin II (AGT, P01019) [466, 2000, 2298], angiotensin-(1-7) (AGT, P01019) [210]</td></tr><tr><td>Agonists</td><td>[Sar¹,Cha⁴]Ang-II [896, 1464] – Rat</td><td>–</td></tr><tr><td>Selective agonists</td><td>L-162,313 [1687], L-163,101 [2175]</td><td>CGP42112 [210], [p-aminoPhe6]ang II [466, 2021] – Rat, compound 21 [2214]</td></tr><tr><td>Antagonists</td><td>saprisartan (pK<sub>d</sub> 9.1) [870] – Rat, 5-oxo-1-2-4-oxadiazol biphenyl (pIC<sub>50</sub> 8.8) [1583] – Rat, 5-butyl-methyl imidazole carboxylate 30 (pIC<sub>50</sub> 8.5) [16], LY303336 (pIC<sub>50</sub> 8.3) [2198], TRV120027 (pK<sub>d</sub> 7.7) [2220]</td><td>saralasin (pIC<sub>50</sub> 9) [371] – Rat</td></tr><tr><td>Selective antagonists</td><td>candesartan (pIC<sub>50</sub> 9.5–9.7) [2199], eprosartan (pIC<sub>50</sub> 8.4–8.8) [543], losartan (pIC<sub>50</sub> 7.4–8.7) [466, 2135], telmisartan (pIC<sub>50</sub> 8.4) [1417], olmesartan (pIC<sub>50</sub> 8.1) [1127]</td><td>PD123177 (pIC<sub>50</sub> 8.5–9.5) [337, 371, 529] – Rat, EMA401 (pIC<sub>50</sub> 8.5–9.3) [599, 1800, 1998], PD123319 (pK<sub>d</sub> 8.7–9.2) [466, 528, 2308]</td></tr><tr><td>Labelled ligands</td><td>[³H]candesartan (Antagonist) (pK<sub>d</sub> 10.3) [594], [¹²⁵I][Sar¹]Ang-II (Agonist) [591] – Rat, [¹²⁵I][Sar¹,Ile⁸]Ang-II (Agonist, Partial agonist) [591] – Rat, [³H]eprosartan (Antagonist) (pK<sub>d</sub> 9.1) [24] – Rat, [³H]losartan (Antagonist) (pK<sub>d</sub> 8.2) [341] – Rat</td><td>[¹²⁵I]CGP42112 (Agonist) [466, 2298, 2299], [¹²⁵I][Sar¹,Ile⁸]Ang-II (Agonist) [2097] – Rat</td></tr><tr><td>Comments</td><td>Telmisartan and candesartan are also reported to be agonists of PPARγ [2040].</td><td>–</td></tr></table>
**Comments:** AT₁ receptors are predominantly coupled to Gq/11, however they are also linked to arrestin recruitment and stimulate G protein-independent arrestin signalling [1332]. Most species express a single AGTR1 gene, but two related *agtr1a* and *agtr1b* receptor genes are expressed in rodents. The AT₂ receptor counteracts several of the growth responses initiated by the AT₁ receptors. The AT₂ receptor is much less abundant than the AT₁ receptor in adult

tissues and is upregulated in pathological conditions. AT₁ receptor antagonists bearing substituted 4-phenylquinoline moieties have been synthesized, which bind to AT₁ receptors with nanomolar affinity and are slightly more potent than *losartan* in functional studies [300]. The antagonist activity of CGP42112 at the AT₂ receptor has also been reported [1596]. The AT₁ and bradykinin B₂ receptors have been proposed to form a heterodimeric complex

[3]. β-Arrestin1 prevents AT₁-B₂ receptor heteromerization [1756]. There is also evidence for an AT₄ receptor that specifically binds angiotensin IV (AGT, P01019) and is located in the brain and kidney. An additional putative endogenous ligand for the AT₄ receptor has been described (LVV-hemorphin (HBB, P68871), a globin decapeptide) [1467].

**Further reading on Angiotensin receptors**

Asada H *et al*. (2018) Crystal structure of the human angiotensin II type 2 receptor bound to an angiotensin II analog. *Nat. Struct. Mol. Biol.* **25**: 570-576 [PMID:29967536]

Karnik SS *et al*. (2015) International Union of Basic and Clinical Pharmacology. XCIX. Angiotensin Receptors: Interpreters of Pathophysiological Angiotensinergic Stimuli [corrected]. *Pharmacol. Rev.* **67**: 754-819 [PMID:26315714]

Singh KD *et al*. (2019) Mechanism of Hormone Peptide Activation of a GPCR: Angiotensin II Activated State of AT₁R Initiated by van der Waals Attraction. *J Chem Inf Model* **59**: 373-385 [PMID:30608150]

Wingler LM *et al*. (2019) Angiotensin Analogs with Divergent Bias Stabilize Distinct Receptor Conformations. *Cell* **176**: 468-478.e11 [PMID:30639099]

Wingler LM *et al*. (2019) Distinctive Activation Mechanism for Angiotensin Receptor Revealed by a Synthetic Nanobody. *Cell* **176**: 479-490.e12 [PMID:30639100]

Zhang H *et al*. (2015) Structure of the Angiotensin receptor revealed by serial femtosecond crystallography. *Cell* **161**: 833-44 [PMID:25913193]
# Apelin receptor

G protein-coupled receptors → Apelin receptor

**Overview:** The apelin receptor (nomenclature as agreed by the NC-IUPHAR Subcommittee on the apelin receptor [1713]) responds to apelin, a 36 amino-acid peptide derived initially from bovine stomach. Apelin-36 (APLN, Q9ULZ1), apelin-13

(APLN, Q9ULZ1) and [Pyr¹]apelin-13 (APLN, Q9ULZ1) are the predominant endogenous ligands which are cleaved from a 77 amino-acid precursor peptide (APLN, Q9ULZ1) by a so far unidentified enzymatic pathway [2106]. A second family of peptides discovered independently and named Elabela [372] or Toddler, that

has little sequence similarity to apelin, is present, and functional at the apelin receptor in the adult cardiovascular system [1668, 2379]. Structure-activity relationship Elabela analogues have been described [1528].

<table><tr><td>Nomenclature</td><td>apelin receptor</td></tr><tr><td>HGNC, UniProt</td><td>APLNR, P35414</td></tr><tr><td>Potency order of endogenous ligands</td><td>[Pyr¹]apelin-13 (APLN, Q9ULZ1) ≥ apelin-13 (APLN, Q9ULZ1) > apelin-36 (APLN, Q9ULZ1) [584, 2106]</td></tr><tr><td>Endogenous agonists</td><td>apelin-13 (APLN, Q9ULZ1) [584, 909, 1428], apelin receptor early endogenous ligand (APELA, P0DMC3) [483], apelin-17 (APLN, Q9ULZ1) [547, 1428], [Pyr¹]apelin-13 (APLN, Q9ULZ1) [1056, 1428], Elabela/Toddler-21 (APELA, P0DMC3) [2378], Elabela/Toddler-32 (APELA, P0DMC3) [2378], apelin-36 (APLN, Q9ULZ1) [584, 909, 1056, 1428], Elabela/Toddler-11 (APELA, P0DMC3) [2378]</td></tr><tr><td>Selective agonists</td><td>CMF-019 (Biased agonist) [1781], MM07 (Biased agonist) [226]</td></tr><tr><td>Antagonists</td><td>MM54 (pK<sub>i</sub> 8.2) [1338]</td></tr><tr><td>Labelled ligands</td><td>[¹²⁵I][Nle<sup>75</sup>,Tyr<sup>77</sup>]apelin-36 (human) (Agonist) [1056], [¹²⁵I][Glp<sup>65</sup>Nle<sup>75</sup>,Tyr<sup>77</sup>]apelin-13 (Agonist) [909], [¹²⁵I](Pyr¹)apelin-13 (Agonist) [1050], [¹²⁵I]apelin-13 (Agonist) [584], [³H](Pyr¹)[Met(0)11]-apelin-13 (Agonist) [1428]</td></tr></table>

**Comments:** Potency order determined for heterologously expressed human apelin receptor (pD₂ values range from 9.5 to 8.6). The apelin receptor may also act as a co-receptor with CD4 for isolates of human immunodeficiency virus, with apelin blocking this

function [323]. A modified apelin-13 peptide, apelin-13(F13A) was reported to block the hypotensive response to apelin in rat *in vivo* [1238], however, this peptide exhibits agonist activity in HEK293 cells stably expressing the recombinant apelin receptor [584]. The

apelin receptor antagonist, MM54, was reported to suppress tumour growth and increase survival in an intracranial xenograft mouse model of glioblastoma [809].

## Further reading on Apelin receptor

Cheng B *et al.* (2012) Neuroprotection of apelin and its signaling pathway. *Peptides* **37**: 171-3 [PMID:22820556]

Langelaan DN *et al.* (2009) Structural insight into G-protein coupled receptor binding by apelin. *Biochemistry* **48**: 537-48 [PMID:19123778]

Mughal A *et al.* (2018) Vascular effects of apelin: Mechanisms and therapeutic potential. *Pharmacol. Ther.* **190**: 139-147 [PMID:29807055]

O'Carroll AM *et al.* (2013) The apelin receptor APJ: journey from an orphan to a multifaceted regulator of homeostasis. *J. Endocrinol.* **219**: R13-35 [PMID:23943882]

Pitkin SL *et al.* (2010) International Union of Basic and Clinical Pharmacology. LXXIV. Apelin receptor nomenclature, distribution, pharmacology, and function. *Pharmacol. Rev.* **62**: 331-42 [PMID:20605969]

Yang P *et al.* (2015) Apelin, Elabela/Toddler, and biased agonists as novel therapeutic agents in the cardiovascular system. *Trends Pharmacol. Sci.* **36**: 560-7 [PMID:26143239]
# Bile acid receptor

G protein-coupled receptors → Bile acid receptor

**Overview:** The bile acid receptor (GPBA) responds to bile acids produced during the liver metabolism of cholesterol. Selective agonists are promising drugs for the treatment of metabolic disorders, such as type II diabetes, obesity and atherosclerosis.

Nomenclature

GPBA receptor

HGNC, UniProt

GPBAR1, Q8TDU6

Potency order of endogenous ligands

lithocholic acid > deoxycholic acid > chenodeoxycholic acid, cholic acid [1055, 1392]

Selective agonists

S-EMCA [1676] – Mouse, betulinic acid [680], oleanolic acid [1871]

**Comments:** The triterpenoid natural product betulinic acid has also been reported to inhibit inflammatory signalling through the NFκB pathway [2081]. Disruption of GPBA expression is reported to protect from cholesterol gallstone formation [2209]. A new series of 5-phenoxy-1,3-dimethyl-1H-pyrazole-4-carboxamides have been reported as highly potent agonists [1313].

## Further reading on Bile acid receptor

Duboc H *et al.* (2014) The bile acid TGR5 membrane receptor: from basic research to clinical application. *Dig Liver Dis* **46**: 302-12 [PMID:24411485]

Lieu T *et al.* (2014) GPBA: a GPCR for bile acids and an emerging therapeutic target for disorders of digestion and sensation. *Br. J. Pharmacol.* **171**: 1156-66 [PMID:24111923]

Lefebvre P *et al.* (2009) Role of bile acids and bile acid receptors in metabolic regulation. *Physiol. Rev.* **89**: 147-91 [PMID:19126757]

van Nierop FS *et al.* (2017) Clinical relevance of the bile acid receptor TGR5 in metabolism. *Lancet Diabetes Endocrinol* **5**: 224-233 [PMID:27639537]

# Bombesin receptors

G protein-coupled receptors → Bombesin receptors

**Overview:** Mammalian bombesin (Bn) receptors comprise 3 subtypes: $BB_1, BB_2, BB_3$ (**nomenclature recommended by the NC-IUPHAR Subcommittee on bombesin receptors**, [**990**]). $BB_1$ and $BB_2$ are activated by the endogenous ligands gastrin-releasing peptide (GRP, P07492) (GRP), neuromedin B (NMB, P08949) (NMB) and GRP-(18-27) (GRP, P07492). Bombesin is a tetradecapeptide, originally derived from amphibians. The

three Bn receptor subtypes couple primarily to the $G_{q/11}$ and $G_{12/13}$ family of G proteins [990]. Each of these receptors is widely distributed in the CNS and peripheral tissues [723, 990, 1721, 1766, 1866, 2420]. Activation of $BB_1$ and $BB_2$ receptors causes a wide range of physiological/pathophysiological actions, including the stimulation of normal and neoplastic tissue growth, smooth-muscle contraction, feeding behavior, secretion and many central

nervous system effects including regulation of circadian rhythm and mediation of pruritus [990, 991, 992, 1359, 1489, 1766]. A physiological role for the $BB_3$ receptor has yet to be fully defined although recently studies suggest an important role in glucose and insulin regulation, metabolic homeostasis, feeding, regulation of body temperature, obesity, diabetes mellitus and growth of normal/neoplastic tissues [723, 1360, 1619, 2345].
<table><tr><td>Nomenclature</td><td>BB<sub>1</sub> receptor</td><td>BB<sub>2</sub> receptor</td><td>BB<sub>3</sub> receptor</td></tr><tr><td>HGNC, UniProt</td><td>NMBR, P28336</td><td>GRPR, P30550</td><td>BRS3, P32247</td></tr><tr><td>Endogenous agonists</td><td>neuromedin B (NMB, P08949) [990, 1766, 2166]</td><td>neuromedin C [2166], gastrin releasing peptide(14-27) (human) [2166]</td><td>–</td></tr><tr><td>Selective agonists</td><td>–</td><td>–</td><td>compound 9g [1398], MK-7725 [373], MK-5046 [1494, 1915], [D-Tyr<sup>6</sup>,Apa-4Cl<sup>11</sup>,Phe<sup>13</sup>,Nle<sup>14</sup>]bombesin-(6-14) [1376], compound 17c [1397], bag-1 [759], compound 22e [836]</td></tr><tr><td>Antagonists</td><td>D-Nal-Cys-Tyr-D-Trp-Lys-Val-Cys-Nal-NH<sub>2</sub> (pIC<sub>50</sub> 6.2–6.6) [722]</td><td>–</td><td>–</td></tr><tr><td>Selective antagonists</td><td>PD 176252 (pIC<sub>50</sub> 9.3–9.8) [722], PD 168368 (pIC<sub>50</sub> 9.3–9.6) [722], dNal-cyc(Cys-Tyr-dTrp-Orn-Val)-Nal-NH<sub>2</sub></td><td>[D-Phe<sup>6</sup>, Leu<sup>13</sup>, Cpa<sup>14</sup>, ψ13-14]bombesin-(6-14) (pK<sub>i</sub> 9.8) [722], JMV641 (pIC<sub>50</sub> 9.3) [2140] – Mouse, [(3-Ph-Pr<sup>6</sup>), His<sup>7</sup>,D-Ala<sup>11</sup>,D-Pro<sup>13</sup>, ψ13-14),Phe<sup>14</sup>]bombesin-(6-14) (pIC<sub>50</sub> 9.2) [722, 1231], JMV594 (pIC<sub>50</sub> 8.9) [1308, 2140] – Mouse, [D-Tpi<sup>6</sup>, Leu<sup>13</sup> ψ(CH<sub>2</sub>NH)-Leu<sup>14</sup>]bombesin-(6-14) (pIC<sub>50</sub> 8.9) [722]</td><td>bantag-1 (pIC<sub>50</sub> 8.6–8.7) [759, 1494], ML-18 (pIC<sub>50</sub> 5.3) [1488]</td></tr><tr><td>Labelled ligands</td><td>[<sup>125</sup>I]BH-NMB (human, mouse, rat) (Agonist), [<sup>125</sup>I][Tyr<sup>4</sup>]bombesin (Agonist)</td><td>[<sup>125</sup>I][D-Tyr<sup>6</sup>]bombesin-(6-13)-methyl ester (Selective Antagonist) (pK<sub>d</sub> 9.3) [1375] – Mouse, [<sup>125</sup>I][Tyr<sup>4</sup>]bombesin (Agonist) [144], [<sup>125</sup>I]GRP (human) (Agonist)</td><td>[<sup>3</sup>H]bag-2 (Agonist) [759] – Mouse, [<sup>125</sup>I][D-Tyr<sup>6</sup>, β-Ala<sup>11</sup>,Phe<sup>13</sup>,Nle<sup>14</sup>]bombesin-(6-14) (Agonist) [1377, 1494]</td></tr></table>

**Comments:** All three human subtypes may be activated by [D-Phe<sup>6</sup>,β-Ala<sup>11</sup>,Phe<sup>13</sup>,Nle<sup>14</sup>]bombesin-(6-14) [1377]. [D-Tyr<sup>6</sup>,Apa-4Cl<sup>11</sup>,Phe<sup>13</sup>,Nle<sup>14</sup>]bombesin-(6-14) has more than 200-fold selectivity for BB<sub>3</sub> receptors over BB<sub>1</sub> and BB<sub>2</sub> [1376, 1377, 1766, 1767].

Further reading on Bombesin receptors

González N *et al.* (2015) Bombesin receptor subtype 3 as a potential target for obesity and diabetes. *Expert Opin. Ther. Targets* **19**: 1153-70 [PMID:26066663]

Jensen RT *et al.* (2008) International Union of Pharmacology. LXVIII. Mammalian bombesin receptors: nomenclature, distribution, pharmacology, signaling, and functions in normal and disease states. *Pharmacol. Rev.* **60**: 1-42 [PMID:18055507]

Maina T *et al.* (2017) Theranostic Prospects of Gastrin-Releasing Peptide Receptor-Radioantagonists in Oncology. *PET Clin* **12**: 297-309 [PMID:28576168]

Moreno P *et al.* (2016) Bombesin related peptides/receptors and their promising therapeutic roles in cancer imaging, targeting and treatment. *Expert Opin. Ther. Targets* **20**: 1055-73 [PMID:26981612]

Qu X *et al.* (2018) Recent insights into biological functions of mammalian bombesin-like peptides and their receptors. *Curr Opin Endocrinol Diabetes Obes* **25**: 36-41 [PMID:29120926]

Ramos-Álvarez I *et al.* (2015) Insights into bombesin receptors and ligands: Highlighting recent advances. *Peptides* **72**: 128-44 [PMID:25976083]
# Bradykinin receptors

G protein-coupled receptors → Bradykinin receptors

**Overview:** Bradykinin (or kinin) receptors (nomenclature as agreed by the **NC-IUPHAR** subcommittee on Bradykinin (kinin) Receptors [1243]) are activated by the endogenous peptides bradykinin (KNG1, P01042) (BK), [des-Arg⁹]bradykinin (KNG1, P01042), Lys-BK (kallidin (KNG1, P01042)), [des-Arg¹⁰]kallidin (KNG1, P01042), [Phospho-Ser⁶]-Bradykinin, T-kinin (KNG1, P01042) (Ile-Ser-BK), [Hyp³]bradykinin (KNG1, P01042) and Lys-[Hyp³]-bradykinin (KNG1, P01042). Variation in pharmacology and activity of B₁ and B₂ receptor antagonists at species orthologs has been documented. Icatibant (Hoe140, Firazir) is approved in North America and Europe for the treatment of acute attacks of hereditary angioedema.

<table><tr><td>Nomenclature</td><td>B₁ receptor</td><td>B₂ receptor</td></tr><tr><td>HGNC, UniProt</td><td>BDKRB1, P46663</td><td>BDKRB2, P30411</td></tr><tr><td>Potency order of endogenous ligands</td><td>[des-Arg¹⁰]kallidin (KNG1, P01042) > [des-Arg⁹]bradykinin (KNG1, P01042) =<br>kallidin (KNG1, P01042) > bradykinin (KNG1, P01042)</td><td>kallidin (KNG1, P01042) > bradykinin (KNG1, P01042) ≫ [des-Arg⁹]bradykinin<br>(KNG1, P01042), [des-Arg¹⁰]kallidin (KNG1, P01042)</td></tr><tr><td>Endogenous agonists</td><td>[des-Arg¹⁰]kallidin (KNG1, P01042) [80, 118, 714, 1012]</td><td>bradykinin (KNG1, P01042)</td></tr><tr><td>Selective agonists</td><td>NG29 [1879], [Sar,D-Phe⁸,des-Arg⁹]bradykinin [1012]</td><td>NG291 [282, 1880], [Hyp³,Tyr(Me)⁸]BK, [Phe⁸,ψ(CH₂-NH)Arg⁹]BK, labradimil<br>[282, 1880]</td></tr><tr><td>Selective antagonists</td><td>B-9958 (pKᵢ 9.2–10.3) [689, 1784], [Leu⁹,des-Arg¹⁰]kallidin (pKᵢ 9.1–9.3) [80,<br>118], SSR240612 (pKᵢ 9.1–9.2) [732], R-954 (pA₂ 8.6) [715], R-715 (pA₂ 8.5) [713]</td><td>icatibant (pKᵢ 10.2) [43], FR173657 (pA₂ 8.2) [1814], anatibant (pKᵢ 8.2) [1742]</td></tr><tr><td>Labelled ligands</td><td>[¹²⁵I]Hpp-desArg¹⁰HOE140 (pK₉ 10), [³H]Lys-[des-Arg⁹]BK (Agonist),<br>[³H]Lys-[Leu⁸][des-Arg⁹]BK (Antagonist)</td><td>[³H]BK (human, mouse, rat) (Agonist) [2318] – Mouse, [³H]NPC17731 (Antagonist)<br>(pK₉ 9.1–9.4) [2423, 2424], [¹²⁵I][Tyr⁸]bradykinin (Agonist)</td></tr></table>

## Further reading on Bradykinin receptors

Campos MM *et al.* (2006) Non-peptide antagonists for kinin B1 receptors: new insights into their therapeutic potential for the management of inflammation and pain. *Trends Pharmacol. Sci.* **27**: 646-51 [PMID:17056130]

Duchene J *et al.* (2009) The kinin B(1) receptor and inflammation: new therapeutic target for cardiovascular disease. *Curr Opin Pharmacol* **9**: 125-31 [PMID:19124274]

Marceau F *et al.* (2004) Bradykinin receptor ligands: therapeutic perspectives. *Nat Rev Drug Discov* **3**: 845-52 [PMID:15459675]

Paquet JL *et al.* (1999) Pharmacological characterization of the bradykinin B2 receptor: inter-species variability and dissociation between binding and functional responses. *Br. J. Pharmacol.* **126**: 1083-90 [PMID:10204994]

Thornton E *et al.* (2010) Kinin receptor antagonists as potential neuroprotective agents in central nervous system injury. *Molecules* **15**: 6598-618 [PMID:20877247]

Whalley ET *et al.* (2012) Discovery and therapeutic potential of kinin receptor antagonists. *Expert Opin Drug Discov* **7**: 1129-48 [PMID:23095011]
# Calcitonin receptors

G protein-coupled receptors → Calcitonin receptors

**Overview:** This receptor family comprises a group of receptors for the calcitonin/CGRP family of peptides. The calcitonin (CT), amylin (AMY), calcitonin gene-related peptide (CGRP) and adrenomedullin (AM) receptors (nomenclature as agreed by the NC-IUPHAR Subcommittee on CGRP, AM, AMY, and CT receptors [830, 1732]) are generated by the genes CALCR (which codes for the CT receptor) and CALCRL (which codes for the calcitonin receptor-like receptor, CLR, previously known as CRLR). Their function and pharmacology are altered in the presence of RAMPs (receptor activity-modifying proteins), which are single TM domain proteins of ca. 130 amino acids, identified as a

family of three members; RAMP1, RAMP2 and RAMP3. There are splice variants of the CT receptor; these in turn produce variants of the AMY receptor [1732], some of which can be potently activated by CGRP. The endogenous agonists are the peptides calcitonin (CALCA, P01258), α-CGRP (CALCA, P06881) (formerly known as CGRP-I), β-CGRP (CALCB, P10092) (formerly known as CGRP-II), amylin (IAPP, P10997) (occasionally called islet-amyloid polypeptide, diabetes-associated polypeptide), adrenomedullin (ADM, P35318) and adrenomedullin 2/intermedin (ADM2, Q7Z4H4). There are species differences in peptide sequences, particularly for the CTs. CTR-stimulating peptide [Pig] (CRSP) is another mem-

ber of the family with selectivity for the CT receptor but it is not expressed in humans [1047]. Olcegepant (also known as BIBN4096BS, pKi10.5) and telcagepant (also known as MK0974, pKi9) are the most selective antagonists available, showing selectivity for CGRP receptors, with a particular preference for those of primate origin. CLR (calcitonin receptor-like receptor) by itself binds no known endogenous ligand, but in the presence of RAMPs it gives receptors for CGRP, adrenomedullin and adrenomedullin 2/intermedin.

<table><thead><tr><th></th><th>CT receptor</th><th>AMY<sub>1</sub> receptor</th><th>AMY<sub>2</sub> receptor</th><th>AMY<sub>3</sub> receptor</th></tr></thead><tbody><tr><td>Nomenclature</td><td>CT receptor</td><td>AMY<sub>1</sub> receptor</td><td>AMY<sub>2</sub> receptor</td><td>AMY<sub>3</sub> receptor</td></tr><tr><td>HGNC, UniProt</td><td>CALCR, P30988</td><td>–</td><td>–</td><td>–</td></tr><tr><td>Subunits</td><td>–</td><td>RAMP1 (Accessory protein), CT receptor</td><td>CT receptor, RAMP2 (Accessory protein)</td><td>CT receptor, RAMP3 (Accessory protein)</td></tr><tr><td>Potency order of endogenous ligands</td><td>calcitonin (salmon) ≥ calcitonin (CALCA, P01258) ≥ amylin (IAPP, P10997), α-CGRP (CALCA, P06881), β-CGRP (CALCB, P10092) > adrenomedullin (ADM, P35318), adrenomedullin 2/intermedin (ADM2, Q7Z4H4)</td><td>calcitonin (salmon) ≥ amylin (IAPP, P10997) ≥ α-CGRP (CALCA, P06881), β-CGRP (CALCB, P10092) > adrenomedullin 2/intermedin (ADM2, Q7Z4H4) ≥ calcitonin (CALCA, P01258) > adrenomedullin (ADM, P35318)</td><td>Poorly defined</td><td>calcitonin (salmon) ≥ amylin (IAPP, P10997) > α-CGRP (CALCA, P06881), β-CGRP (CALCB, P10092) ≥ adrenomedullin 2/intermedin (ADM2, Q7Z4H4) ≥ calcitonin (CALCA, P01258) > adrenomedullin (ADM, P35318)</td></tr><tr><td>Endogenous agonists</td><td>calcitonin (CALCA, P01258) [35, 68, 827, 1183, 1263, 1517]</td><td>α-CGRP (CALCA, P06881) [827, 1182, 1183, 1263, 2241], amylin (IAPP, P10997) [705], β-CGRP (CALCB, P10092)</td><td>amylin (IAPP, P10997) [705]</td><td>amylin (IAPP, P10997) [705]</td></tr><tr><td>Sub/family-selective agonists</td><td>pramlintide [705]</td><td>pramlintide [705]</td><td>–</td><td>pramlintide [705]</td></tr><tr><td>Sub/family-selective antagonists</td><td>CT-(8-32) (salmon) (pK<sub>d</sub> 9) [874], AC187 (pK<sub>i</sub> 7.2) [827]</td><td>AC187 (pK<sub>i</sub> 8) [827], CT-(8-32) (salmon) (pK<sub>i</sub> 7.8) [827], olcegepant (pK<sub>d</sub> 7.2) [2241]</td><td>–</td><td>CT-(8-32) (salmon) (pK<sub>i</sub> 7.9) [827], AC187 (pK<sub>i</sub> 7.7) [827]</td></tr><tr><td>Labelled ligands</td><td>[<sup>125</sup>I]CT (human) (Agonist), [<sup>125</sup>I]CT (salmon) (Agonist)</td><td>[<sup>125</sup>I]αCGRP (human) (Agonist), [<sup>125</sup>I]BH-AMY (rat, mouse) (Agonist)</td><td>[<sup>125</sup>I]BH-AMY (rat, mouse) (Agonist)</td><td>[<sup>125</sup>I]BH-AMY (rat, mouse) (Agonist)</td></tr></tbody></table>
<table><thead><tr><th></th><th></th><th></th><th></th><th></th></tr></thead><tbody><tr><td>Nomenclature</td><td>calcitonin receptor-like receptor</td><td>CGRP receptor</td><td>AM<sub>1</sub> receptor</td><td>AM<sub>2</sub> receptor</td></tr><tr><td>HGNC, UniProt</td><td>CALCRL, Q16602</td><td>-</td><td>-</td><td>-</td></tr><tr><td>Subunits</td><td>-</td><td>calcitonin receptor-like receptor, RAMP1 (Accessory protein)</td><td>calcitonin receptor-like receptor, RAMP2 (Accessory protein)</td><td>calcitonin receptor-like receptor, RAMP3 (Accessory protein)</td></tr><tr><td>Potency order of endogenous ligands</td><td>-</td><td>α-CGRP (CALCA, P06881), β-CGRP (CALCB, P10092) > adrenomedullin (ADM, P35318) ≥ adrenomedullin 2/intermedin (ADM2, Q7Z4H4) > amylin (IAPP, P10997) ≥ calcitonin (salmon)</td><td>adrenomedullin (ADM, P35318) > adrenomedullin 2/intermedin (ADM2, Q7Z4H4) > α-CGRP (CALCA, P06881), β-CGRP (CALCB, P10092), amylin (IAPP, P10997) > calcitonin (salmon)</td><td>adrenomedullin (ADM, P35318) ≥ adrenomedullin 2/intermedin (ADM2, Q7Z4H4) ≥ α-CGRP (CALCA, P06881), β-CGRP (CALCB, P10092) > amylin (IAPP, P10997) > calcitonin (salmon)</td></tr><tr><td>Endogenous agonists</td><td>-</td><td>β-CGRP (CALCB, P10092) [23, 1426], α-CGRP (CALCA, P06881) [23, 1426]</td><td>adrenomedullin (ADM, P35318) [23, 1426]</td><td>adrenomedullin (ADM, P35318) [23, 623]</td></tr><tr><td>Antagonists</td><td>-</td><td>olcegepant (pK<sub>i</sub> 10.7–11) [512, 828, 829, 1022, 1368], telcagepant (pK<sub>i</sub> 9.1) [1857]</td><td>-</td><td>-</td></tr><tr><td>Selective antagonists</td><td>-</td><td>-</td><td>AM-(22-52) (human) (pK<sub>i</sub> 7–7.8) [829]</td><td>AM-(22-52) (human)</td></tr><tr><td>Labelled ligands</td><td>-</td><td>[<sup>125</sup>I]αCGRP (human) (Agonist), [<sup>125</sup>I]αCGRP (mouse, rat) (Agonist)</td><td>[<sup>125</sup>I]AM (rat) (Agonist)</td><td>[<sup>125</sup>I]AM (rat) (Agonist)</td></tr></tbody></table>

**Comments:** It is important to note that a complication with the interpretation of pharmacological studies with AMY receptors in transfected cells is that most of this work has likely used a mixed population of receptors, encompassing RAMP-coupled CTR as well as CTR alone. This means that although in binding assays human calcitonin (CALCA, P01258) has low affinity for <sup>125</sup>I-AMY binding sites, cells transfected with CTR and RAMPs can display potent CT functional responses. Transfection of human CTR with any RAMP can generate receptors with a high affinity for both salmon CT and AMY and varying affinity for different antagonists [388, 827, 828]. The major human CTR splice variant (hCT<sub>(a)</sub>, which does not contain an insert) with RAMP1 (i.e. the AMY<sub>1(a)</sub> recep-

tor) has a high affinity for CGRP [2241], unlike hCT<sub>(a)</sub>-RAMP3 (i.e. AMY<sub>3(a)</sub> receptor) [388, 827]. However, the AMY receptor phenotype is RAMP-type, splice variant and cell-line-dependent [1495, 1750, 2134]. Emerging data suggests that AMY<sub>1</sub> could be a second CGRP receptor [826].

The ligands described have limited selectivity. Adrenomedullin has appreciable affinity for CGRP receptors. CGRP can show significant cross-reactivity at AMY receptors and AM<sub>2</sub> receptors. Adrenomedullin 2/intermedin also has high affinity for the AM<sub>2</sub> receptor [903]. CGRP-(8-37) acts as an antagonist of CGRP (pK<sub>i</sub> 8) and inhibits some AM and AMY responses (pK<sub>i</sub> 6-7). It is weak at CT receptors. Human AM-(22-52) has some selectivity towards AM

receptors, but with modest potency (pK<sub>i</sub> 7), limiting its use [829]. Olcegepant shows the greatest selectivity between receptors but still has significant affinity for AMY<sub>1</sub> receptors [2241].

G<sub>s</sub> is a prominent route for effector coupling for CLR and CTR but other pathways (e.g. Ca<sup>2+</sup>, ERK, Akt), and G proteins can be activated [2240]. There is evidence that CGRP-RCP (a 148 amino-acid hydrophilic protein, ASL (P04424) is important for the coupling of CLR to adenylyl cyclase [578].

[<sup>125</sup>I>-Salmon CT is the most common radioligand for CT receptors but it has high affinity for AMY receptors and is also poorly reversible.

## Further reading on Calcitonin receptors

* Hay DL et al. (2018) Update on the pharmacology of calcitonin/CGRP family of peptides: IUPHAR Review 25. Br. J. Pharmacol. 175: 3-17 [PMID:29059473]

* Hay DL et al. (2016) Receptor Activity-Modifying Proteins (RAMPs): New Insights and Roles. Annu. Rev. Pharmacol. Toxicol. 56: 469-87 [PMID:26514202]

* Kato J et al. (2015) Bench-to-bedside pharmacology of adrenomedullin. Eur. J. Pharmacol. 764: 140-8 [PMID:26144371]

* Russell FA et al. (2014) Calcitonin gene-related peptide: physiology and pathophysiology. Physiol. Rev. 94: 1099-142 [PMID:25287861]

* Russo AF. (2015) Calcitonin gene-related peptide (CGRP): a new target for migraine. Annu. Rev. Pharmacol. Toxicol. 55: 533-52 [PMID:25340934]
# Calcium-sensing receptor

G protein-coupled receptors → Calcium-sensing receptor

**Overview:** The calcium-sensing receptor (CaS, provisional nomenclature as recommended by NC-IUPHAR [612]) responds to multiple endogenous ligands, including extracellular calcium and other divalent/trivalent cations, polyamines and polycationic peptides, L-amino acids (particularly L-Trp and L-Phe), glutathione and various peptide analogues, ionic

strength and extracellular pH (reviewed in [1228]). While divalent/trivalent cations, polyamines and polycations are CaS receptor agonists [252, 1754], L-amino acids, glutamyl peptides, ionic strength and pH are allosteric modulators of agonist function [411, 612, 885, 1752, 1753]. Indeed, L-amino acids have been identified as "co-agonists", with both concomitant calcium and

L-amino acid binding required for full receptor activation [682, 2416]. The sensitivity of the CaS receptor to primary agonists is increased by elevated extracellular pH [295] or decreased extracellular ionic strength [1753]. This receptor bears no sequence or structural relation to the plant calcium receptor, also called CaS.

<table><tr><td>Nomenclature</td><td>CaS receptor</td></tr><tr><td>HGNC, UniProt</td><td>CASR, P41180</td></tr><tr><td>Amino-acid rank order of potency</td><td>L-phenylalanine, L-tryptophan, L-histidine > L-alanine > L-serine, L-proline, L-glutamic acid > L-aspartic acid (not L-lysine, L-arginine, L-leucine and L-isoleucine) [411]</td></tr><tr><td>Cation rank order of potency</td><td>Gd<sup>3+</sup> > Ca<sup>2+</sup> > Mg<sup>2+</sup> [252]</td></tr><tr><td>Glutamyl peptide rank order of potency</td><td>S-methylglutathione ≈ γ-Glu-Val-Gly > glutathione > γ-Glu-Cys [243, 1621, 2256]</td></tr><tr><td>Polyamine rank order of potency</td><td>spermine > spermidine > putrescine [1754]</td></tr><tr><td>Allosteric modulators</td><td>ATF 936 (Negative) (pIC<sub>50</sub> 8.9) [2302], encaleret (Negative) (pIC<sub>50</sub> 7.9) [1956], SB-423562 (Negative) (pIC<sub>50</sub> 7.1) [1176], ronacaleret (Negative) (pIC<sub>50</sub> 6.5–6.8) [101], NPS 2143 (Negative) (pK<sub>B</sub> 6.2–6.7) [459, 1226, 1229], cinacalcet (Positive) (pK<sub>B</sub> 5.9–6.6) [414, 459, 1226, 1229], tecalcet (Positive) (pK<sub>B</sub> 6.2–6.6) [414, 459], AC265347 (Positive) (pK<sub>B</sub> 6.3–6.4) [414, 1226], calhex 231 (Negative) (pIC<sub>50</sub> 6.4) [1699], calindol (Positive) (pK<sub>B</sub> 6.3) [414]</td></tr></table>

**Comments:** The CaS receptor has a number of physiological functions, but it is best known for its central role in parathyroid and renal regulation of extracellular calcium homeostasis [798]. This is seen most clearly in patients with loss-of-function CaS receptor mutations who develop familial hypocalciuric hypercalcaemia (heterozygous mutations) or neonatal severe hyperparathyroidism (heterozygous, compound heterozygous or homozygous mutations) [798] and in *Casr* null mice [339, 885], which exhibit similar increases in PTH secretion and blood calcium levels. Gain-of-function CaS mutations are associated with autosomal dominant hypocalcaemia and Bartter syndrome type V [798].

The CaS receptor primarily couples to $G_{q/11}$, $G_{12/13}$ and $G_{i/0}$ [459, 693, 922, 2124], but in some cell types can couple to $G_s$ [1370]. However, the CaS receptor can form heteromers with Class C $GABA_B$ [340, 362] and mGlu1/5 receptors [651], which may introduce further complexity in its signalling capabilities.

Multiple other small molecule chemotypes are positive and negative allosteric modulators of the CaS receptor [1078, 1565]. Further, *etelcalcetide* is a novel peptide positive allosteric modulator of the receptor [2243]. Agonists and positive allosteric modulators of the CaS receptor are termed Type I and II calcimimetics, respectively, and can suppress parathyroid hormone (PTH

(PTH, P01270)) secretion [1567]. Negative allosteric modulators are called calcilytics and can act to increase PTH (PTH, P01270) secretion [1566].

Where functional $pK_B$ values are provided for allosteric modulators, this refers to ligand affinity determined in an assay that measures a functional readout of receptor activity (i.e. a receptor signalling assay), as opposed to affinity determined in a radioligand binding assay. The functional $pK_B$ may differ depending on the signalling pathway studied. Consult the 'More detailed page' for the assay description, as well as other functional readouts.

## Further reading on Calcium-sensing receptor

* Brown EM. (2013) Role of the calcium-sensing receptor in extracellular calcium homeostasis. *Best Pract. Res. Clin. Endocrinol. Metab.* 27: 333-43 [PMID:23856263]

* Conigrave AD et al. (2013) Calcium-sensing receptor (CaSR): pharmacological properties and signaling pathways. *Best Pract. Res. Clin. Endocrinol. Metab.* 27: 315-31 [PMID:23856262]

* Hannan FM et al. (2018) The calcium-sensing receptor in physiology and in calcitropic and noncalcitropic diseases. *Nat Rev Endocrinol* 15: 33-51 [PMID:30443043]

* Nemeth EF et al. (2018) Discovery and Development of Calcimimetic and Calcilytic Compounds. *Prog Med Chem* 57: 1-86 [PMID:29680147]
# Cannabinoid receptors

G protein-coupled receptors → Cannabinoid receptors

**Overview:** Cannabinoid receptors (nomenclature as agreed by the **NC-IUPHAR** Subcommittee on Cannabinoid Receptors [1692]) are activated by endogenous ligands that include N-arachidonoylethanolamine (anandamide), N-homo-γ-linolenoylethanolamine, N-docosatetra-7,10,13,16-enoylethanolamine and 2-arachidonoylglycerol. Potency determinations of endogenous

agonists at these receptors are complicated by the possibility of differential susceptibility of endogenous ligands to enzymatic conversion [38].

There are currently three licenced cannabinoid medicines each of which contains a compound that can activate CB₁ and CB₂ receptors [1690]. Two of these medicines were developed to sup-

press nausea and vomiting produced by chemotherapy. These are nabilone (Cesamet®), a synthetic CB₁/CB₂ receptor agonist, and synthetic Δ⁹-tetrahydrocannabinol (Marinol®; dronabinol), which can also be used as an appetite stimulant. The third medicine, Sativex®, contains mainly Δ⁹-tetrahydrocannabinol and cannabidiol, both extracted from cannabis, and is used to treat multiple sclerosis and cancer pain.

<table><tr><td>Nomenclature</td><td>CB₁ receptor</td><td>CB₂ receptor</td></tr><tr><td>HGNC, UniProt</td><td>CNR1, P21554</td><td>CNR2, P34972</td></tr><tr><td>Agonists</td><td>HU-210 [590, 1960], CP55940 [590, 1824, 1960], WIN55212-2 [590, 1959, 1960], Δ⁹-tetrahydrocannabinol (Partial agonist) [590, 1960], cannabinol (Partial agonist) [590, 1960]</td><td>HU-210 [590, 1796, 1960], WIN55212-2 [590, 1959, 1960], CP55940 [590, 1824, 1960], Δ⁹-tetrahydrocannabinol (Partial agonist) [121, 590, 1796, 1960]</td></tr><tr><td>Selective agonists</td><td>arachidonyl-2-chloroethylamide [872] – Rat, arachidonylcyclopropylamide [872] – Rat, O-1812 [489] – Rat, R-(+)-methanandamide [1073] – Rat</td><td>JWH-133 [930, 1691], L-759,633 [663, 1824], AM1241 [2381], L-759,656 [663, 1824], HU-308 [806]</td></tr><tr><td>Selective antagonists</td><td>rimonabant (pKᵢ 7.9–8.7) [589, 590, 1804, 1835, 1960], AM6545 (pKᵢ 8.5) [217], AM251 (pKᵢ 8.1) [1196] – Rat, AM281 (pKᵢ 7.9) [1195] – Rat, LY320135 (pKᵢ 6.9) [589]</td><td>SR144528 (pKᵢ 8.3–9.2) [1805, 1824], AM-630 (pKᵢ 7.5) [1824]</td></tr><tr><td>Allosteric modulators</td><td>GAT100 (Negative) (pEC₅₀ 7.7) [1172], ZCZ011 (Positive) (pEC₅₀ 6.3) [943] – Mouse, GAT211 (Positive) [1205], cannabidiol (Negative) [1204]</td><td>pepcan-12 (Positive) (pKᵢ ~7.3) [1701], compound C2 (Positive) [643]</td></tr><tr><td>Labelled ligands</td><td>[³H]rimonabant (Antagonist) (pKₐ 8.9–10) [228, 880, 1025, 1698, 1806, 1972, 2118] – Rat –</td><td></td></tr></table>

**Comments:** Both CB₁ and CB₂ receptors may be labelled with [³H]CP55940 (0.5 nM; [1960]) and [³H]WIN55212-2 (2–2.4 nM; [1987, 2013]). Anandamide is also an agonist at vanilloid receptors (TRPV1) and PPARs [1608, 2444]. There is evidence for an

allosteric site on the CB₁ receptor [1735]. All of the compounds listed as antagonists behave as inverse agonists in some bioassay systems [1692]. For some cannabinoid receptor ligands, additional pharmacological targets that include GPR55 and GPR119 have

been identified [1692]. Moreover, GPR18, GPR55 and GPR119, although showing little structural similarity to CB₁ and CB₂ receptors, respond to endogenous agents that are structurally similar to the endogenous cannabinoid ligands [1692].
## Further reading on Cannabinoid receptors

Howlett AC et al. (2002) International Union of Pharmacology. XXVII. Classification of cannabinoid receptors. *Pharmacol. Rev.* **54**: 161-202 [PMID:12037135]

Pertwee RG. (2010) Receptors and channels targeted by synthetic cannabinoid receptor agonists and antagonists. *Curr. Med. Chem.* **17**: 1360-81 [PMID:20166927]

Pertwee RG et al. (2010) International Union of Basic and Clinical Pharmacology. LXXIX. Cannabinoid receptors and their ligands: beyond CB_1 and CB_2. *Pharmacol. Rev.* **62**: 588-631 [PMID:21079038]

# Chemerin receptors

G protein-coupled receptors → Chemerin receptors

**Overview:** Nomenclature for the chemerin receptors is presented as **recommended by NC-IUPHAR [455, 1065]**). The chemoattractant protein and adipokine, **chemerin (RARRES2, Q99969)**, has been shown to be the endogenous ligand for both chemerin

family receptors. Chemerin₁ was the founding family member, and when GPR1 was de-orphanised it was re-named Chemerin₂ [1065]. Chemerin₁ is also activated by the lipid-derived, anti-inflammatory ligand resolvin E1 (RvE1), which is formed via the

sequential metabolism of EPA by aspirin-modified cyclooxygenase and lipoxygenase [66, 67]. In addition, two GPCRs for resolvin D1 (RvD1) have been identified: FPR2/ALX, the lipoxin A₄ receptor, and GPR32, an orphan receptor [1153].

Nomenclature **chemerin receptor 1**

chemerin receptor 2

Common abbreviation **Chemerin₁**

Chemerin₂

HGNC, UniProt **CMKLR1, Q99788**

GPR1, P46091

Potency order of endogenous ligands **resolvin E1 > chemerin C-terminal peptide > 18R-HEPE > EPA [66]**

–

Endogenous agonists **–**

chemerin (RARRES2, Q99969) [109]

Selective agonists **resolvin E1**

–

Labelled ligands **[³H]resolvin E1 (Agonist) [66, 67]**

–

Comments **–**

Reported to act as a co-receptor for HIV [1952]. See review [455] for discussion of pairing with chemerin.

**Comments:** CCX832 (structure not disclosed) is a selective antagonist, pKᵢ=9.2 [1066].

## Further reading on Chemerin receptors

Kennedy AJ et al. (2018) International Union of Basic and Clinical Pharmacology CIII: Chemerin Receptors CMKLR1 (Chemerin1) and GPR1 (Chemerin2) Nomenclature, Pharmacology, and Function. *Pharmacol. Rev.* **70**: 174-196 [PMID:29279348]

Shin WJ et al. (2018) Mechanisms and Functions of Chemerin in Cancer: Potential Roles in Therapeutic Intervention. *Front Immunol* **9**: 2772 [PMID:30555465]
# Chemokine receptors

G protein-coupled receptors → Chemokine receptors

**Overview:** Chemokine receptors (nomenclature as agreed by the NC-IUPHAR Subcommittee on Chemokine Receptors [90, 1524, 1525]) comprise a large subfamily of 7TM proteins that bind one or more chemokines, a large family of small cytokines typically possessing chemotactic activity for leukocytes. Additional hematopoietic and non-hematopoietic roles have been identified for many chemokines in the areas of embryonic development, immune cell proliferation, activation and death, viral infection, and as antibiotics, among others. Chemokine receptors can be divided by function into two main groups: G protein-coupled chemokine receptors, which mediate leukocyte trafficking, and "Atypical chemokine receptors", which may signal through non-G protein-coupled mechanisms and act as chemokine scavengers to downregulate inflammation or shape

chemokine gradients [90].

Chemokines in turn can be divided by structure into four subclasses by the number and arrangement of conserved cysteines. CC (also known as β-chemokines; n= 28), CXC (also known as α-chemokines; n= 17) and CX3C (n= 1) chemokines all have four conserved cysteines, with zero, one and three amino acids separating the first two cysteines respectively. C chemokines (n= 2) have only the second and fourth cysteines found in other chemokines. Chemokines can also be classified by function into homeostatic and inflammatory subgroups. Most chemokine receptors are able to bind multiple high-affinity chemokine ligands, but the ligands for a given receptor are almost always restricted to the same structural subclass. Most chemokines bind to more than one recep-

tor subtype. Receptors for inflammatory chemokines are typically highly promiscuous with regard to ligand specificity, and may lack a selective endogenous ligand. G protein-coupled chemokine receptors are named according to the class of chemokines bound, whereas ACKR is the root acronym for atypical chemokine receptors [91]. There can be substantial cross-species differences in the sequences of both chemokines and chemokine receptors, and in the pharmacology and biology of chemokine receptors. Endogenous and microbial non-chemokine ligands have also been identified for chemokine receptors. Many chemokine receptors function as HIV co-receptors, but CCR5 is the only one demonstrated to play an essential role in HIV/AIDS pathogenesis. The tables include both standard chemokine receptor names [2401] and aliases.

<table><tr><td>Nomenclature</td><td>CCR1</td><td>CCR2</td><td>CCR3</td></tr><tr><td>HGNC, UniProt</td><td>CCR1, P32246</td><td>CCR2, P41597</td><td>CCR3, P51677</td></tr><tr><td>Endogenous agonists</td><td>CCL3 (CCL3, P10147) [375, 406, 862, 2443], CCL23 (CCL23, P55773) [375], CCL5 (CCL5, P13501) [406, 862], CCL7 (CCL7, P80098) [375, 775], CCL15 (CCL15, Q16663) [423], CCL14 (CCL14, Q16627) [375], CCL13 (CCL13, Q99616), CCL8 (CCL8, P80075)</td><td>CCL2 (CCL2, P13500) [423, 1335, 1461, 1658, 2167], CCL13 (CCL13, Q99616) [1335, 2167], CCL7 (CCL7, P80098) [423, 1335, 2167], CCL11 (CCL11, P51671) (Partial agonist) [1335, 1658], CCL16 (CCL16, O15467)</td><td>CCL13 (CCL13, Q99616) [1505, 2167], CCL24 (CCL24, O00175) [1505, 1658], CCL5 (CCL5, P13501) [449], CCL7 (CCL7, P80098) [449], CCL11 (CCL11, P51671) [531, 1108, 1505, 1849, 2167], CCL26 (CCL26, Q9Y258) [1108, 1505, 1658], CCL15 (CCL15, Q16663) [423], CCL28 (CCL28, Q9NRJ3), CCL8 (CCL8, P80075)</td></tr><tr><td>Agonists</td><td>—</td><td>—</td><td>CCL11 (Mouse) [449]</td></tr><tr><td>Endogenous antagonists</td><td>CCL4 (CCL4, P13236) (pK<sub>i</sub> 7.1–7.8) [375, 406]</td><td>CCL26 (CCL26, Q9Y258) (pIC<sub>50</sub> 8.5) [1658]</td><td>CXCL10 (CXCL10, P02778), CXCL11 (CXCL11, O14625), CXCL9 (CXCL9, Q07325)</td></tr><tr><td>Selective antagonists</td><td>BX 471 (pK<sub>i</sub> 8.2–9) [1274], compound 2b-1 (pIC<sub>50</sub> 8.7) [1552], UCB35625 (pIC<sub>50</sub> 8) [1849], CP-481,715 (pK<sub>d</sub> 8) [708]</td><td>GSK Compound 34 (pK<sub>i</sub> 7.6)</td><td>banyu (I) (Inverse agonist) (pK<sub>i</sub> 8.5) [2247], SB328437 (pK<sub>i</sub> 8.4), BMS compound 87b (pK<sub>i</sub> 8.1) [2232]</td></tr><tr><td>Labelled ligands</td><td>[125I]CCL7 (human) (Agonist) [140], [125I]CCL3 (human) (Agonist) [140, 720, 1870], [125I]CCL5 (human) (Agonist) [1870]</td><td>[125I]CCL2 (human) (Agonist), [125I]CCL7 (human) (Agonist)</td><td>[125I]CCL11 (human) (Antagonist) (pK<sub>d</sub> 8.3) [2247], [125I]CCL5 (human) (Agonist), [125I]CCL7 (human) (Agonist)</td></tr></table>
<table><thead><tr><th></th><th></th><th></th><th></th><th></th><th></th><th></th><th></th><th></th></tr></thead><tbody><tr><td>Nomenclature</td><td>CCR4</td><td>CCR5</td><td>CCR6</td><td>CCR7</td><td>CCR8</td><td>CCR9</td><td>CCR10</td></tr><tr><td>HGNC, UniProt</td><td>CCR4, P51679</td><td>CCR5, P51681</td><td>CCR6, P51684</td><td>CCR7, P32248</td><td>CCR8, P51685</td><td>CCR9, P51686</td><td>CCR10, P46092</td></tr><tr><td>Endogenous agonists</td><td>CCL22 (CCL22, O00626) [947], CCL17 (CCL17, Q92583) [947]</td><td>CCL5 (CCL5, P13501) [87, 1547, 1833], CCL4 (CCL4, P13236) [1547, 1833], CCL8 (CCL8, P80075) [1833], CCL3 (CCL3, P10147) [1547, 1833, 2443], CCL11 (CCL11, P51671) [175], CCL2 (CCL2, P13500) [1547], CCL14 (CCL14, Q16627) [1547], CCL16 (CCL16, O15467)</td><td>CCL20 (CCL20, P78556) [22, 86, 1730], beta-defensin 4A (DEFB4A DEFB4B, O15263) [2373]</td><td>CCL21 (CCL21, O00585) [2399], CCL19 (CCL19, Q99731) [1640, 2398, 2399]</td><td>CCL1 (CCL1, P22362) [441, 819, 948], CCL8 (Mouse)</td><td>CCL25 (CCL25, O15444)</td><td>CCL27 (CCL27, Q9Y4X3) [901], CCL28 (CCL28, Q9NRJ3)</td></tr><tr><td>Agonists</td><td>vMIP-III</td><td>R5-HIV-1 gp120</td><td>–</td><td>–</td><td>vMIP-1 [441, 948]</td><td>–</td><td>–</td></tr><tr><td>Endogenous antagonists</td><td>–</td><td>CCL7 (CCL7, P80098) (pK<sub>i</sub> 7.5) [1547]</td><td>–</td><td>–</td><td>–</td><td>–</td><td>–</td></tr><tr><td>Antagonists</td><td>–</td><td>vicriviroc (pK<sub>i</sub> 9.1) [2043], ancriviroc (pK<sub>i</sub> 7.8–8.7) [1348, 1647, 2043]</td><td>–</td><td>–</td><td>–</td><td>–</td><td>–</td></tr><tr><td>Selective antagonists</td><td>compound 8ic (pIC<sub>50</sub> 7.7) [2396]</td><td>E913 (pIC<sub>50</sub> 8.7) [1349], aplaviroc (pK<sub>i</sub> 8.5) [1348], maraviroc (pIC<sub>50</sub> 8.1) [1547], TAK-779 (pK<sub>i</sub> 7.5) [1348], MRK-1 [1175] – Rat</td><td>–</td><td>–</td><td>vMCC-1 (pIC<sub>50</sub> 9.4) [441]</td><td>–</td><td>–</td></tr><tr><td>Selective allosteric modulators</td><td>–</td><td>–</td><td>–</td><td>–</td><td>–</td><td>vercirnon (Antagonist) (pIC<sub>50</sub> 8.2) [2244]</td><td>–</td></tr><tr><td>Antibodies</td><td>mogamulizumab (Inhibition) [58, 1962]</td><td>–</td><td>–</td><td>–</td><td>–</td><td>–</td><td>–</td></tr><tr><td>Labelled ligands</td><td>[125I]CCL17 (human) (Agonist), [125I]CCL27 (human) (Agonist)</td><td>[125I]CCL4 (human) (Agonist) [1547], [125I]CCL3 (human) (Agonist), [125I]CCL5 (human) (Agonist), [125I]CCL8 (human) (Agonist)</td><td>[125I]CCL20 (human) (Agonist) [742]</td><td>[125I]CCL19 (human) (Agonist), [125I]CCL21 (human) (Agonist) [989]</td><td>[125I]CCL1 (human) (Agonist) [948, 1819]</td><td>[125I]CCL25 (human) (Agonist)</td><td>–</td></tr></tbody></table>
<table><thead><tr><th></th><th></th><th></th><th></th><th></th><th></th><th></th><th></th><th></th></tr></thead><tbody><tr><td>Nomenclature</td><td>CXCR1</td><td>CXCR2</td><td>CXCR3</td><td>CXCR4</td><td>CXCR5</td><td>CXCR6</td><td>CX3CR1</td><td></td></tr><tr><td>HGNC, UniProt</td><td>CXCR1, P25024</td><td>CXCR2, P25025</td><td>CXCR3, P49682</td><td>CXCR4, P61073</td><td>CXCR5, P32302</td><td>CXCR6, O00574</td><td>CX3CR1, P49238</td><td></td></tr><tr><td>Endogenous agonists</td><td>CXCL8 (CXCL8, P10145) [157, 783, 1239, 2316, 2336], CXCL6 (CXCL6, P80162) [2341]</td><td>CXCL1 (CXCL1, P09341) [783, 1239, 2336], CXCL8 (CXCL8, P10145) [157, 783, 1239, 2316, 2336], CXCL7 (PPBP, P02775) [20], CXCL3 (CXCL3, P19876) [20], CXCL2 (CXCL2, P19875) [20], CXCL5 (CXCL5, P42830) [20], CXCL6 (CXCL6, P80162) [2341]</td><td>CXCL11 (CXCL11, O14625) [845], CXCL10 (CXCL10, P02778) [845, 2285], CXCL9 (CXCL9, Q07325) [845, 2285]</td><td>CXCL12α (CXCL12, P48061) [861, 1311], CXCL12β (CXCL12, P48061) [861]</td><td>CXCL13 (CXCL13, O43927) [111]</td><td>CXCL16 (CXCL16, Q9H2A7) [2309]</td><td>CX3CL1 (CX3CL1, P78423) [664]</td><td></td></tr><tr><td>Agonists</td><td>vCXCL1 [1334], HIV-1 matrix protein p17 [698]</td><td>vCXCL1 [1334], HIV-1 matrix protein p17 [698]</td><td>–</td><td>–</td><td>–</td><td>–</td><td>–</td><td></td></tr><tr><td>Selective agonists</td><td>–</td><td>–</td><td>–</td><td>ALX40-4C (Partial agonist) [2426], X4-HIV-1 gp120</td><td>–</td><td>–</td><td>–</td><td></td></tr><tr><td>Endogenous antagonists</td><td>–</td><td>–</td><td>CCL11 (CCL11, P51671) (pK<sub>i</sub> 7.2) [2285], CCL7 (CCL7, P80098) (pK<sub>i</sub> 6.6) [2285]</td><td>–</td><td>–</td><td>–</td><td>–</td><td></td></tr><tr><td>Antagonists</td><td>–</td><td>–</td><td>–</td><td>plerixafor (pK<sub>i</sub> 7) [2426]</td><td>–</td><td>–</td><td>–</td><td></td></tr><tr><td>Selective antagonists</td><td>–</td><td>navarixin (pIC<sub>50</sub> 10.3) [90, 535], danirixin (pIC<sub>50</sub> 7.9) [1457], SB 225002 (pIC<sub>50</sub> 7.7) [2296], elubirixin (pIC<sub>50</sub> 7.7) [90], SX-517 (pIC<sub>50</sub> 7.2) [1347]</td><td>–</td><td>T134 (pIC<sub>50</sub> 8.4) [2096], mavorixafor (pIC<sub>50</sub> 7.9) [1980], HIV-Tat</td><td>–</td><td>–</td><td>–</td><td></td></tr><tr><td>Allosteric modulators</td><td>reparixin (Negative) (pIC<sub>50</sub> 9) [157]</td><td>reparixin (Negative) (pIC<sub>50</sub> 6.4) [157]</td><td>–</td><td>–</td><td>–</td><td>–</td><td>–</td><td></td></tr><tr><td>Labelled ligands</td><td>[125I]CXCL8 (human) (Agonist) [783, 1802]</td><td>[125I]CXCL8 (human) (Agonist) [783, 1802], [125I]CXCL1 (human) (Agonist), [125I]CXCL5 (human) (Agonist), [125I]CXCL7 (human) (Agonist)</td><td>[125I]CXCL10 (human) (Agonist), [125I]CXCL11 (human) (Agonist)</td><td>[125I]CXCL12α (human) (Agonist) [491, 861]</td><td>[125I]CXCL13 (mouse) (Agonist) [245] – Mouse</td><td>[125I]CXCL16 (human) (Agonist)</td><td>[125I]CX<sub>3</sub>CL1 (human) (Agonist)</td><td></td></tr></tbody></table>
<table><tr><td>Nomenclature</td><td>XCR1</td><td>ACKR1</td><td>ACKR2</td><td>ACKR3</td><td>ACKR4</td><td>CCRL2</td></tr><tr><td>HGNC, UniProt</td><td>XCR1, P46094</td><td>ACKR1, Q16570</td><td>ACKR2, O00590</td><td>ACKR3, P25106</td><td>ACKR4, Q9NPB9</td><td>CCRL2, O00421</td></tr><tr><td>Endogenous ligands</td><td>–</td><td>CXCL5 (CXCL5, P42830),<br/>CXCL6 (CXCL6, P80162),<br/>CXCL8 (CXCL8, P10145),<br/>CXCL11 (CXCL11, O14625),<br/>CCL2 (CCL2, P13500),<br/>CCL5 (CCL5, P13501),<br/>CCL7 (CCL7, P80098),<br/>CCL11 (CCL11, P51671),<br/>CCL14 (CCL14, Q16627),<br/>CCL17 (CCL17, Q92583)</td><td>–</td><td>–</td><td>–</td><td>chemerin C-terminal peptide,<br/>CCL19 (CCL19, Q99731)<br/>[109]</td></tr><tr><td>Endogenous agonists</td><td>XCL1 (XCL1, P47992) [619],<br/>XCL2 (XCL2, Q9UBD3)<br/>[619]</td><td>–</td><td>CCL2 (CCL2, P13500),<br/>CCL3 (CCL3, P10147),<br/>CCL4 (CCL4, P13236),<br/>CCL5 (CCL5, P13501),<br/>CCL7 (CCL7, P80098),<br/>CCL8 (CCL8, P80075),<br/>CCL11 (CCL11, P51671),<br/>CCL13 (CCL13, Q99616),<br/>CCL14 (CCL14, Q16627),<br/>CCL17 (CCL17, Q92583),<br/>CCL22 (CCL22, O00626)</td><td>CXCL12α (CXCL12,<br/>P48061) [741, 2015],<br/>CXCL11 (CXCL11, O14625)</td><td>CCL19 (CCL19, Q99731)<br/>[2276], CCL25 (CCL25,<br/>O15444) [2276], CCL21<br/>(CCL21, O00585) [2276]</td><td>–</td></tr><tr><td>Comments</td><td>XCL1 cannot be iodinated,<br/>but a secreted alkaline<br/>phophatase (SEAP)-XCL1<br/>fusion peptide can be used<br/>as a probe at XCR1.</td><td>ACKR1 is used by<br/>Plasmodium vivax and<br/>Plasmodium knowlesi for<br/>entering erythrocytes.</td><td>–</td><td>Several lines of evidence<br/>have suggested that CGRP<br/>and adrenomedullin could<br/>be ligands for ACKR3;<br/>however, classical direct<br/>binding to the receptor has<br/>not yet been convincingly<br/>demonstrated [2074].</td><td>–</td><td>–</td></tr></table>

**Comments:** Specific chemokine receptors facilitate cell entry by microbes, such as ACKR1 for *Plasmodium vivax*, and CCR5 and CXCR4 for HIV-1. Virally encoded chemokine receptors are known (e.g. US28, a homologue of CCR1 from human cytomegalovirus and ORF74, which encodes a homolog of CXCR2 in *Herpesvirus saimiri* and gamma-Herpesvirus-68), but their role

in viral life cycles is not established. Viruses can exploit or subvert the chemokine system by producing chemokine antagonists and scavengers. Three chemokine receptor antagonists have now been approved by the FDA: 1) the CCR5 antagonist maraviroc (Pfizer) for treatment of HIV/AIDS in patients with CCR5-using strains; and 2) the CXCR4 antagonist plerixafor (Sanofi) for hematopoietic

stem cell mobilization with G-CSF (CSF3, P09919) in patients undergoing transplantation in the context of chemotherapy for Hodgkins' Disease and multiple myeloma; and 3) the CCR4 blocking antibody Poteligeo (mogamulizumab-kpkc, Kyowa Kirin, Inc.) for mycosis fungoides or Sezary syndrome.
Further reading on Chemokine receptors

Bachelerie F et al. (2015) An atypical addition to the chemokine receptor nomenclature: IUPHAR Review 15. *Br. J. Pharmacol.* **172**: 3945-9 [PMID:25958743]

Koelink PJ et al. (2012) Targeting chemokine receptors in chronic inflammatory diseases: an extensive review. *Pharmacol. Ther.* **133**: 1-18 [PMID:21839114]

Murphy PM. (2002) International Union of Pharmacology. XXX. Update on chemokine receptor nomenclature. *Pharmacol. Rev.* **54**: 227-9 [PMID:12037138]

Murphy PM et al. (2000) International Union of Pharmacology. XXII. Nomenclature for chemokine receptors. *Pharmacol. Rev.* **52**: 145-176 [PMID:10699158]

Scholten DJ et al. (2012) Pharmacological modulation of chemokine receptor function. *Br. J. Pharmacol.* **165**: 1617-43 [PMID:21699506]

Cholecystokinin receptors

G protein-coupled receptors → Cholecystokinin receptors

**Overview:** Cholecystokinin receptors (nomenclature as agreed by the NC-IUPHAR Subcommittee on CCK receptors [1598]) are activated by the endogenous peptides cholecystokinin-8 (CCK-8 (CCK, P06307)), CCK-33 (CCK, P06307), CCK-58 (CCK, P06307) and gastrin (gastrin-17 (GAST, P01350)). There are only two distinct subtypes of CCK receptors, CCK₁ and CCK₂ receptors [1139, 2263], with some alternatively spliced forms most often identified in neoplastic cells. The CCK receptor subtypes are distinguished by their peptide selectivity, with the CCK₁ receptor requiring the carboxyl-terminal heptapeptide-amide that includes a sulfated tyrosine for high affinity and potency, while the CCK₂ receptor requires only the

carboxyl-terminal tetrapeptide shared by each CCK and gastrin peptides. These receptors have characteristic and distinct distributions, with both present in both the central nervous system and peripheral tissues.

<table><tr><td>Nomenclature</td><td>CCK<sub>1</sub> receptor</td><td>CCK<sub>2</sub> receptor</td></tr><tr><td>HGNC, UniProt</td><td>CCKAR, P32238</td><td>CCKBR, P32239</td></tr><tr><td>Potency order of endogenous ligands</td><td>CCK-8 (CCK, P06307), CCK-58 (CCK, P06307), CCK-39 (CCK), CCK-33 (CCK, P06307) &gt;&gt; gastrin-17 (GAST, P01350), desulfated cholecystokinin-8 &gt; CCK-4 (CCK, P06307)</td><td>CCK-8 (CCK, P06307), CCK-39 (CCK), CCK-33 (CCK, P06307), CCK-58 (CCK, P06307) &gt; gastrin-17 (GAST, P01350), desulfated cholecystokinin-8, CCK-4 (CCK, P06307)</td></tr><tr><td>Endogenous agonists</td><td>CCK-33 (CCK, P06307), CCK-39 (CCK), CCK-58 (CCK, P06307), CCK-8 (CCK, P06307)</td><td>desulfated cholecystokinin-8 [1242], gastrin-17 (GAST, P01350) [931] – Mouse, CCK-4 (CCK, P06307) [957], desulfated gastrin-14 (GAST, P01350), desulfated gastrin-17 (GAST, P01350), desulfated gastrin-34 (GAST, P01350), desulfated gastrin-71 (GAST, P01350), gastrin-14 (GAST, P01350), gastrin-34 (GAST, P01350), gastrin-71 (GAST, P01350)</td></tr><tr><td>Selective agonists</td><td>A-71623 [74] – Rat, JMV180 [1068], GW-5823 [851]</td><td>RB-400 [138] – Rat, PBC-264 [974] – Rat</td></tr><tr><td>Antagonists</td><td>lintitript (pIC<sub>50</sub> 8.3) [733]</td><td>–</td></tr><tr><td>Selective antagonists</td><td>devazepide (pIC<sub>50</sub> 9.7) [931] – Rat, T-0632 (pIC<sub>50</sub> 9.6) [2103] – Rat, PD-140548 (pIC<sub>50</sub> 8.6) [1977] – Rat, lorglumide (pIC<sub>50</sub> 6.7–8.2) [931, 963] – Rat</td><td>YF-476 (pIC<sub>50</sub> 9.7) [218, 2094], GV150013 (pIC<sub>50</sub> 9.4) [2180], L-740093 (pIC<sub>50</sub> 9.2) [1590], YM-022 (pIC<sub>50</sub> 9.2) [1590], JNJ-26070109 (pIC<sub>50</sub> 8.5) [1510], L-365260 (pIC<sub>50</sub> 8.4) [1242], RP73870 (pIC<sub>50</sub> 8) [1291] – Rat, LY262691 (pIC<sub>50</sub> 7.5) [1773] – Rat</td></tr><tr><td>Labelled ligands</td><td>[<sup>3</sup>H]devazepide (Antagonist) (pK<sub>d</sub> 9.7) [338], [<sup>125</sup>I]DTyr-Gly-[(Nle28,31)CCK-26-33 (Agonist)] [1731]</td><td>[<sup>3</sup>H]PD140376 (Antagonist) (pK<sub>i</sub> 9.7–10) [935] – Guinea pig, [<sup>125</sup>I]PD142308 (Antagonist) (pK<sub>d</sub> 9.6) [905] – Guinea pig, [<sup>125</sup>I]DTyr-Gly-[(Nle28,31)CCK-26-33 (Agonist)] [1731], [<sup>125</sup>I]gastrin (Agonist), [<sup>3</sup>H]gastrin (Agonist), [<sup>3</sup>H]L365260 (Antagonist) (pK<sub>d</sub> 8.2–8.5) [1590], [<sup>125</sup>I]-BDZ<sub>2</sub> (Antagonist) (pK<sub>i</sub> 8.4) [27]</td></tr></table>
**Comments:** While a cancer-specific CCK receptor has been postulated to exist, which also might be responsive to incompletely processed forms of CCK (Gly-extended forms), this has never been isolated. An alternatively spliced form of the CCK₂ receptor in which intron 4 is retained, adding 69 amino acids to the intracellular

loop 3 (ICL3) region, has been described to be present particularly in certain neoplasms where mRNA mis-splicing has been commonly observed [1995], but it is not clear that this receptor splice form plays a special role in carcinogenesis. Another alternative splicing event for the CCK₂ receptor was reported [2012],

with alternative donor sites in exon 4 resulting in long (452 amino acids) and short (447 amino acids) forms of the receptor differing by five residues in ICL3, however, no clear functional differences have been observed.

## Further reading on Cholecystokinin receptors

Ballaz S. (2017) The unappreciated roles of the cholecystokinin receptor CCK(1) in brain functioning. *Rev Neurosci* **28**: 573-585 [PMID:28343167]

Cawston EE et al. (2010) Therapeutic potential for novel drugs targeting the type 1 cholecystokinin receptor. *Br. J. Pharmacol.* **159**: 1009-21 [PMID:19922535]

Dockray GJ. (2009) Cholecystokinin and gut-brain signalling. *Regul. Pept.* **155**: 6-10 [PMID:19345244]

Dufresne M et al. (2006) Cholecystokinin and gastrin receptors. *Physiol. Rev.* **86**: 805-47 [PMID:16816139]

# Class Frizzled GPCRs

G protein-coupled receptors → Class Frizzled GPCRs

**Overview:** Receptors of the Class Frizzled (FZD, nomenclature as agreed by the NC-IUPHAR subcommittee on the Class Frizzled GPCRs [1902]), are GPCRs originally identified in *Drosophila* [332], which are highly conserved across species. While SMO shows structural resemblance to the 10 FZDs, it is functionally separated as it mediates effects in the Hedgehog signalling pathway [1902]. FZDs are activated by WNTs, which are cysteine-rich lipoglycoproteins with fundamental functions in oncogeny and tissue homeostasis. FZD signalling was initially divided into two pathways, being either dependent on the accumulation of the transcription regulator β-catenin (*CTNNB1*, *P35222*) or being β-catenin-independent (often referred to as canonical vs. non-canonical WNT/FZD signalling, respectively). WNT stimulation of FZDs can, in cooperation with the low density lipoprotein

receptors *LRP5* (O75197) and *LRP6* (O75581), lead to the inhibition of a constitutively active destruction complex, which results in the accumulation of β-catenin and subsequently its translocation to the nucleus. β-Catenin, in turn, modifies gene transcription by interacting with TCF/LEF transcription factors. β-Catenin-independent FZD signalling is far more complex with regard to the diversity of the activated pathways. WNT/FZD signalling can lead to the activation of heterotrimeric G proteins [496, 1694, 1903], the elevation of intracellular calcium [1989], activation of cGMP-specific PDE6 [21] and elevation of cAMP as well as RAC-1, JNK, Rho and Rho kinase signalling [802]. Novel resonance energy transfer-based tools have allowed the study of the GPCR-like nature of FZDs in greater detail. Upon ligand stimulation, FZDs undergo conformational changes and signal via

heterotrimeric G proteins [2332, 2333]. Furthermore, the phosphoprotein Dishevelled constitutes a key player in WNT/FZD signalling. Importantly, FZDs exist in at least two distinct conformational states that regulate the pathway selection [2333]. As with other GPCRs, members of the Frizzled family are functionally dependent on the arrestin scaffolding protein for internalization [354], as well as for β-catenin-dependent [262] and independent [263, 1084] signalling. The pattern of cell signalling is complicated by the presence of additional ligands, which can enhance or inhibit FZD signalling (secreted Frizzled-related proteins (sFRP), Wnt-inhibitory factor (WIF1, Q9Y5W5) (WIF), sclerostin (SOST, Q9BQB4) or Dickkopf (DKK)), as well as modulatory (co)-receptors with Ryk, ROR1, ROR2 and Kremen, which may also function as independent signalling proteins.
<table><tr><td>Nomenclature</td><td>FZD<sub>1</sub></td><td>FZD<sub>2</sub></td><td>FZD<sub>3</sub></td><td>FZD<sub>4</sub></td><td>FZD<sub>5</sub></td></tr><tr><td>HGNC, UniProt</td><td>FZD1, Q9UP38</td><td>FZD2, Q14332</td><td>FZD3, Q9NPG1</td><td>FZD4, Q9ULV1</td><td>FZD5, Q13467</td></tr><tr><td>Allosteric modulators</td><td>–</td><td>–</td><td>–</td><td>FzM1.8 (Negative) (pIC<sub>50</sub> 5.5–7.8) [679], FzM1.8 (Positive) (pEC<sub>50</sub> 6.4) [1799], FzM1 (Negative) (pIC<sub>50</sub> 6.2) [679, 1799]</td><td>–</td></tr></table>

<table><tr><td>Antibodies</td><td>vantictumab (Antagonist) (pIC<sub>50</sub> ~9.1) [771]</td><td>vantictumab (Antagonist) (pIC<sub>50</sub> ~9) [771]</td><td>–</td><td>–</td><td>vantictumab (Antagonist) (pIC<sub>50</sub> ~9) [771]</td></tr></table>

<table><tr><td>Comments</td><td>–</td><td>–</td><td>–</td><td>–</td><td>IgG-2919 and IgG-2921 are FZD<sub>5</sub> antibodies that have exhibited antitumour activities <i>in vitro</i> and <i>in vivo</i> (inhibiting the growth of RNF43-mutant pancreatic ductal adenocarcinoma cells/xenograft tumours), by blocking autocrine Wnt-β-catenin signalling in these mutant, FZD<sub>5</sub>-dependent cells [2029].</td></tr></table>

<table><tr><td>Nomenclature</td><td>FZD<sub>6</sub></td><td>FZD<sub>7</sub></td><td>FZD<sub>8</sub></td><td>FZD<sub>9</sub></td><td>FZD<sub>10</sub></td></tr><tr><td>HGNC, UniProt</td><td>FZD6, O60353</td><td>FZD7, O75084</td><td>FZD8, Q9H461</td><td>FZD9, O00144</td><td>FZD10, Q9ULW2</td></tr><tr><td>Selective antagonists</td><td>–</td><td>Fz7-21 (pIC<sub>50</sub> 7) [1589]</td><td>–</td><td>–</td><td>–</td></tr><tr><td>Antibodies</td><td>–</td><td>vantictumab (Antagonist) (pIC<sub>50</sub> ~9) [771]</td><td>vantictumab (Antagonist) (pIC<sub>50</sub> ~8) [771]</td><td>–</td><td>–</td></tr><tr><td>Comments</td><td>–</td><td>–</td><td>FZD8-Fc/OMP-54F28 is a FZD<sub>8</sub> antagonist [477].</td><td>–</td><td>Radio-labelled murine monoclonal antibody MAb 92-13 has been used to demonstrate the therapeutic potential of targeting FZD<sub>10</sub>-positive tumours [639].</td></tr></table>
<table><tr><td>Nomenclature</td><td>SMO</td></tr><tr><td>HGNC, UniProt</td><td>SMO, Q99835</td></tr><tr><td>Agonists</td><td>SMO agonist (SAG) [350] – Mouse, purmorphamine [1978]</td></tr><tr><td>Antagonists</td><td>MRT-92 (pK<sub>d</sub> 9.5) [890], SANT-1 (pK<sub>i</sub> 7.7) [350] – Mouse, cyclopamine-KAAD (pIC<sub>50</sub> 7.7) [2080] – Mouse, cyclopamine (pIC<sub>50</sub> ~7) [2162] – Mouse</td></tr><tr><td>Selective antagonists</td><td>vismodegib (pK<sub>i</sub> 7.8) [2252]</td></tr><tr><td>Allosteric modulators</td><td>GSA-10 (Positive) (pEC<sub>50</sub> 5.9) [726]</td></tr><tr><td>Comments</td><td>SANT-3 and SANT-4 are SMO antagonists [350].</td></tr></table>

**Comments:** There is limited knowledge about WNT/FZD specificity and which molecular entities determine the signalling outcome of a specific WNT/FZD pair. Understanding of the FZD and SMO coupling to G proteins is incomplete, but progress have been made [72, 496, 1083, 1374, 1808, 1945, 2229, 2332]. There is also a scarcity of information on basic pharmacological characteristics of FZDs, such as binding constants, ligand specificity or concentration-response relationships [1081]. Development of pharmacological tools for SMO has been facilitated by successful crystallization of several SMO structures [278, 924, 2250, 2251, 2279, 2427]. The recently solved FZD4 in apo state has provided first insight into FZD transmembranous organization [2380].

## Ligands associated with FZD signalling

**WNTs:** Wnt-1 (WNT1, P04628), Wnt-2 (WNT2, P09544) (also known as Int-1-related protein), Wnt-2b (WNT2B, Q93097) (also known as WNT-13), Wnt-3 (WNT3, P56703), Wnt-3a (WNT3A, P56704), Wnt-4 (WNT4, P56705), Wnt-5a (WNT5A, P41221) (pEC50 7.7-8.9 [2332]), Wnt-5b (WNT5B, Q9H1J7), Wnt-6 (WNT6, Q9Y6F9), Wnt-7a (WNT7A, O00755), Wnt-7b (WNT7B, P56706), Wnt-8a (WNT8A, Q9H1J5), Wnt-8b (WNT8B, Q93098), Wnt-9a (WNT9A, O14904) (also known as WNT-14), Wnt-9b (WNT9B, O14905) (also known as WNT-15 or WNT-14b), Wnt-10a (WNT10A, Q9GZT5), Wnt-10b (WNT10B, O00744) (also known as WNT-12), Wnt-11 (WNT11, O96014) and Wnt-16 (WNT16, Q9UBV4).

**Extracellular proteins that interact with FZDs:** norrin (NDP, Q00604), R-spondin-4 (RSPO4, Q2I0M5), sFRP-1 (SFRP1, Q8N474), sFRP-2 (SFRP2, Q96HF1), sFRP-3 (FRZB, Q92765), sFRP-4 (SFRP4, Q6FHJ7), sFRP-5 (SFRP5, Q6FHJ7).

**Extracellular proteins that interact with WNTs or LRPs:** Dickkopf 1 (DKK1, O94907), WIF1 (Q9Y5W5), sclerostin (SOST, Q9BQB4), kremen 1 (KREMEN1, Q96MU8) and kremen 2 (KREMEN2, Q8NCW0)

**Small exogenous ligands:** Foxy-5 [2075], Box-5 [988], UM206 [1189], and XWnt8 (P28026) also known as mini-Wnt8.

**Ligands associated with SMO signalling:** cholesterol, oxysterols [278, 1325, 1761].

## Further reading on Class Frizzled GPCRs

* Angers S *et al.* (2009) Proximal events in Wnt signal transduction. *Nat. Rev. Mol. Cell Biol.* **10**: 468-77 [PMID:19536106]

* Schulte G. (2015) Frizzleds and WNT/β-catenin signaling–The black box of ligand-receptor selectivity, complex stoichiometry and activation kinetics. *Eur. J. Pharmacol.* **763**: 191-5 [PMID:26003275]

* Schulte G *et al.* (2018) Frizzleds as GPCRs - More Conventional Than We Thought! *Trends Pharmacol. Sci.* **39**: 828-842 [PMID:30049420]

* van Amerongen R. (2012) Alternative Wnt pathways and receptors. *Cold Spring Harb Perspect Biol* **4**: [PMID:22935904]

* Wang Y *et al.* (2016) Frizzled Receptors in Development and Disease. *Curr. Top. Dev. Biol.* **117**: 113-39 [PMID:26969975]
# Complement peptide receptors

G protein-coupled receptors → Complement peptide receptors

**Overview:** Complement peptide receptors (nomenclature as agreed by the **NC-IUPHAR** subcommittee on Complement peptide receptors [1114]) are activated by the endogenous 75 amino-acid anaphylatoxin polypeptides C3a (C3, P01024) and C5a (C5, P01031), generated upon stimulation of the complement cascade. C3a and C5a exert their functions through binding to their receptors (C3aR and C5aR), causing cell activation and triggering cellular degranulation that contributes to the local inflammation.

<table><thead><tr><th></th><th></th><th></th><th></th></tr></thead><tbody><tr><td>Nomenclature</td><td>C3a receptor</td><td>C5a<sub>1</sub> receptor</td><td>C5a<sub>2</sub> receptor</td></tr><tr><td>HGNC, UniProt</td><td>C3AR1, Q16581</td><td>C5AR1, P21730</td><td>C5AR2, Q9P296</td></tr><tr><td>Potency order of endogenous ligands</td><td>C3a (C3, P01024) > C5a (C5, P01031) [45]</td><td>C5a (C5, P01031), C5a des-Arg (C5) > C3a (C3, P01024) [45]</td><td>–</td></tr><tr><td>Endogenous agonists</td><td>–</td><td>ribosomal protein S19 (RPS19, P39019) [2363]</td><td>–</td></tr><tr><td>Agonists</td><td>compound 17 [1786], compound 21 [1785], casoxin C [2082, 2402], albutensin A [2086, 2402], oryzatensin [1003, 2083, 2402]</td><td>NDT9513727 (Inverse agonist) [244], N-methyl-Phe-Lys-Pro-D-Cha-Cha-D-Arg-CO<sub>2</sub>H [1054, 1136], lactomedin 1 [2276, 2402]</td><td>–</td></tr><tr><td>Selective agonists</td><td>–</td><td>–</td><td>P59 (Biased agonist) [434], P32 (Biased agonist) [434]</td></tr><tr><td>Antagonists</td><td>SB290157 (pIC<sub>50</sub> 7.6) [44], compound 4 (pIC<sub>50</sub> 5.9) [1785]</td><td>avacopan (pIC<sub>50</sub> 9.7) [134], W54011 (pK<sub>i</sub> 8.7) [2056], DF2593A (pIC<sub>50</sub> 8.3) [1499], AcPhe-Orn-Pro-D-Cha-Trp-Arg (pIC<sub>50</sub> 7.9) [2323], N-methyl-Phe-Lys-Pro-D-Cha-Trp-D-Arg-CO<sub>2</sub>H (pIC<sub>50</sub> 7.2) [1136]</td><td>–</td></tr><tr><td>Labelled ligands</td><td>[125I]C3a (human) (Agonist) [342]</td><td>[125I]C5a (human) (Agonist) [929]</td><td>[125I]C5a (human) (Agonist)</td></tr><tr><td>Comments</td><td>C3a-C3aR signalling plays a crucial role in inhibiting neural progenitor cell proliferation during neurodevelopment, playing a critical role in the normal development of the mammalian brain [426].</td><td>–</td><td>–</td></tr></tbody></table>

**Comments:** SB290157 has also been reported to have agonist properties at the C3a receptor [1396]. The putative chemoattractant receptor termed C5a<sub>2</sub> (also known as GPR77, C5L2) binds [125I]C5a with no clear signalling function, but has a putative role opposing inflammatory responses [291, 655, 673]. Binding to this site may be displaced with the rank order C5a des-Arg (C5) > C5a (C5, P01031) [291, 1631] while there is controversy over the ability

of C3a (C3, P01024) and C3a des Arg (C3, P01024) to compete [902, 1029, 1030, 1631]. C5a<sub>2</sub> appears to lack G protein signalling and has been termed a decoy receptor [1910]. However, C5a<sub>2</sub> does recruit arrestin after ligand binding, which might provide a signalling pathway for this receptor [103, 2192], and forms heteromers with C5a<sub>1</sub>. C5a, but not C5a-des Arg, induces upregulation of heteromer formation between complement C5a receptors C5a<sub>1</sub> and

C5a<sub>2</sub> [433]. There are also reports of pro-inflammatory activity of C5a<sub>2</sub>, mediated by HMGB1, but the signaling pathway that underlies this is currently unclear (reviewed in [1271]). More recently, work in T cells has shown that C5a<sub>1</sub> and C5a<sub>2</sub> act in opposition to each other and that altering the equilibrium between the two receptors, by differential expression or production of C5a-des Arg (which favours C5a<sub>2</sub>), can affect the final cellular response [61].
Further reading on Complement peptide receptors

Arbore G *et al.* (2016) A novel "complement-metabolism-inflammasome axis" as a key regulator of immune cell effector function. *Eur. J. Immunol.* **46**: 1563-73 [PMID:27184294]

Coulthard LG *et al.* (2018) Complement C3a receptor modulates embryonic neural progenitor cell proliferation and cognitive performance. *Mol. Immunol.* **101**: 176-181 [PMID:30449309]

Laumonnier Y *et al.* (2017) Novel insights into the expression pattern of anaphylatoxin receptors in mice and men. *Mol. Immunol.* **89**: 44-58 [PMID:28600003]

Li R *et al.* (2013) C5L2: a controversial receptor of complement anaphylatoxin, C5a. *FASEB J.* **27**: 855-64 [PMID:23239822]

Monk PN *et al.* (2007) Function, structure and therapeutic potential of complement C5a receptors. *Br. J. Pharmacol.* **152**: 429-48 [PMID:17603557]

Reichhardt MP *et al.* (2018) Intracellular complement activation-An alarm raising mechanism? *Semin. Immunol.* **38**: 54-62 [PMID:29631809]

Corticotropin-releasing factor receptors

G protein-coupled receptors → Corticotropin-releasing factor receptors

**Overview:** Corticotropin-releasing factor (CRF, nomenclature as agreed by the **NC-IUPHAR** subcommittee on Corticotropin-releasing Factor Receptors [824]) receptors are activated by the endogenous peptides corticotrophin-releasing hormone (CRH, P06850), a 41 amino-acid peptide, urocortin 1 (UCN, P55089), 40 amino-acids,

urocortin 2 (UCN2, Q96RP3), 38 amino-acids and urocortin 3 (UCN3, Q969E3), 38 amino-acids. CRF₁ and CRF₂ receptors are activated non-selectively by CRH and UCN. CRF₂ receptors are selectively activated by UCN2 and UCN3. Binding to CRF receptors can be conducted using radioligands [¹²⁵I]Tyr⁰-CRF or

[¹²⁵I]Tyr⁰-sauvagine with $K_d$ values of 0.1-0.4 nM. CRF₁ and CRF₂ receptors are non-selectively antagonized by α-helical CRF, D-Phe-CRF-(12-41) and astressin. CRF₁ receptors are selectively antagonized by small molecules NBI27914, R121919, antalarmin, CP 154,526, CP 376,395. CRF₂ receptors are selectively antagonized by antisauvagine and astressin 2B.

Nomenclature CRF₁ receptor

HGNC, UniProt CRHR1, P34998

Endogenous agonists urocortin 1 (UCN, P55089) [451, 453, 508], corticotrophin-releasing hormone (CRH, P06850) [353, 450, 453, 508, 1648, 2212]

Antagonists SSR125543A ($pK_i$ 8.7) [766], astressin ($pK_i$ 8.7) [1812]

Selective antagonists CP 154,526 (pIC₅₀ 9.3-10.4) [1328] – Rat, DMP696 ($pK_i$ 8.3-9) [835], NBI27914 ($pK_i$ 8.3-9) [346], R121919 ($pK_i$ 8.3-9) [2442], antalarmin ($pK_i$ 8.3-9) [2278], CP 376,395 (pIC₅₀ 8.3) [355] – Rat, CRA1000 (pIC₅₀ 6.4-7.1) [330]

CRF₂ receptor

CRHR2, Q13324

urocortin 2 (UCN2, Q96RP3) [451], urocortin 3 (UCN3, Q969E3) [451]

astressin (pIC₅₀ 9.2) [1810]

antisauvagine ($pK_d$ 8.8-9.6) [453], K41498 ($pK_i$ 9.2) [1211], astressin 2B (pIC₅₀ 8.9) [1810], K31440 ($pK_i$ 8.7-8.8) [1846]

**Comments:** A CRF binding protein has been identified (CRHBP, P24387) to which both corticotrophin-releasing hormone (CRH, P06850) and urocortin 1 (UCN, P55089) bind with high affinities, which has been suggested to bind and inactivate circulating corticotrophin-releasing hormone (CRH, P06850) [1686].

Further reading on Corticotropin-releasing factor receptors

Deussing JM *et al.* (2018) The Corticotropin-Releasing Factor Family: Physiology of the Stress Response. *Physiol. Rev.* **98**: 2225-2286 [PMID:30109816]

Grammatopoulos DK. (2012) Insights into mechanisms of corticotropin-releasing hormone receptor signal transduction. *Br. J. Pharmacol.* **166**: 85-97 [PMID:21883143]

Hauger RL *et al.* (2003) International Union of Pharmacology. XXXVI. Current status of the nomenclature for receptors for corticotropin-releasing factor and their ligands. *Pharmacol Rev.* **55**: 21-26 [PMID:12615952]

Liapakis G *et al.* (2011) Members of CRF family and their receptors: from past to future. *Curr. Med. Chem.* **18**: 2583-600 [PMID:21568890]
# Dopamine receptors

G protein-coupled receptors → Dopamine receptors

**Overview:** Dopamine receptors (nomenclature as agreed by the **NC-IUPHAR Subcommittee on Dopamine Receptors [1906]** ) are commonly divided into D₁-like (D₁ and D₅) and D₂-like (D₂, D₃ and D₄) families, where the endogenous agonist is dopamine.

<table><tr><td>Nomenclature</td><td>D₁ receptor</td><td>D₂ receptor</td></tr><tr><td>HGNC, UniProt</td><td>DRD1, P21728</td><td>DRD2, P14416</td></tr><tr><td>Sub/family-selective labelled ligands</td><td>[125I]SCH23982 (Antagonist) (pK<sub>d</sub> 9.5) [478], [³H]SCH-23390 (Antagonist) (pK<sub>d</sub> 9.5) [2435]</td><td>[³H]spiperone (Antagonist) (pK<sub>d</sub> 10.2) [266, 888, 2433] – Rat</td></tr><tr><td>Endogenous agonists</td><td>dopamine [2060, 2132]</td><td>dopamine [272, 628, 1876]</td></tr><tr><td>Agonists</td><td>fenoldopam [2132]</td><td>rotigotine [497], cabergoline (Partial agonist) [1451], aripiprazole (Partial agonist) [2410], bromocriptine [628, 1451, 1876], MLS1547 (Biased agonist) [627], ropinirole [843], apomorphine (Partial agonist) [272, 628, 1451, 1876, 2006], pramipexole [1446, 1876], benzquinamide [744]</td></tr><tr><td>Sub/family-selective agonists</td><td>A68930 [1569], SKF-38393 (Partial agonist) [2060, 2132]</td><td>quinpirole [272, 1446, 1665, 2006, 2008, 2196]</td></tr><tr><td>Selective agonists</td><td>SKF-83959 (Biased agonist) [413], A77636 [1844], SKF-81297 [50] – Rat</td><td>sumanirole [1415]</td></tr><tr><td>Antagonists</td><td>flupentixol (pK<sub>i</sub> 7–8.4) [2060, 2132]</td><td>blonanserin (pK<sub>i</sub> 9.9) [1611], pipotiazine (pK<sub>i</sub> 9.7) [2007], perphenazine (pK<sub>i</sub> 8.9–9.6) [1156, 1920], risperidone (pK<sub>i</sub> 9.4) [70], perospirone (pK<sub>i</sub> 9.2) [1919], trifluoperazine (pK<sub>i</sub> 8.9–9) [1156, 1920], quetiapine (pK<sub>i</sub> 7.2) [70]</td></tr><tr><td>Sub/family-selective antagonists</td><td>SCH-23390 (pK<sub>i</sub> 7.4–9.5) [2060, 2132], SKF-83566 (pK<sub>i</sub> 9.5) [2060], ecopipam (pK<sub>i</sub> 8.3) [2133]</td><td>haloperidol (pK<sub>i</sub> 7.4–8.8) [628, 1341, 1446, 2006, 2133]</td></tr><tr><td>Selective antagonists</td><td>–</td><td>L-741,626 (pK<sub>i</sub> 7.9–8.5) [755, 1171], domperidone (pK<sub>i</sub> 7.9–8.4) [628, 2006], raclopride (pK<sub>i</sub> 8) [1453], ML321 (pK<sub>i</sub> 7) [2347, 2348]</td></tr><tr><td>Labelled ligands</td><td>–</td><td>[³H]raclopride (Antagonist) (pK<sub>d</sub> 8.9) [1184] – Rat</td></tr></table>
<table><thead><tr><th></th><th></th><th></th><th></th></tr></thead><tbody><tr><td>Nomenclature</td><td>D<sub>3</sub> receptor</td><td>D<sub>4</sub> receptor</td><td>D<sub>5</sub> receptor</td></tr><tr><td>HGNC, UniProt</td><td>DRD3, P35462</td><td>DRD4, P21917</td><td>DRD5, P21918</td></tr><tr><td>Sub/family-selective labelled ligands</td><td>–</td><td>[<sup>3</sup>H]spiperone (Antagonist) (pK<sub>d</sub> 9.5) [866, 2196]</td><td>[<sup>3</sup>H]SCH-23390 (Antagonist) (pK<sub>d</sub> 9.2) [1797]</td></tr><tr><td>Endogenous agonists</td><td>dopamine [272, 628, 1876, 2008]</td><td>dopamine [2196]</td><td>dopamine [2060]</td></tr><tr><td>Agonists</td><td>pramipexole [1446, 1876], bromocriptine (Partial agonist) [628, 1451, 1876], ropinirole [843], apomorphine (Partial agonist) [272, 628, 1451, 1876, 2006]</td><td>apomorphine (Partial agonist) [1451]</td><td>–</td></tr><tr><td>Sub/family-selective agonists</td><td>quinpirole [272, 1446, 1453, 1665, 1876, 2006, 2008, 2196]</td><td>quinpirole [1451, 1665, 2196]</td><td>A68930 [1569]</td></tr><tr><td>Selective agonists</td><td>PD 128907 [1745, 1876]</td><td>PD168,077 (Partial agonist) [1141] – Rat, A412997 [1491] – Rat, A412997 [1491]</td><td>–</td></tr><tr><td>Antagonists</td><td>perospirone (pK<sub>i</sub> 9.6) [2006], sertindole (pK<sub>i</sub> 8–8.8) [70, 1901, 1920], prochlorperazine (pK<sub>i</sub> 8.4) [79], (-)-sulpiride (pK<sub>i</sub> 6.7–7.7) [628, 2006, 2102], loxapine (pK<sub>i</sub> 7.7) [1920], domperidone (pK<sub>i</sub> 7.1–7.6) [628, 2006], promazine (pK<sub>i</sub> 6.8) [273]</td><td>perospirone (pK<sub>i</sub> 10.1) [1921], sertindole (pK<sub>i</sub> 7.8–9.1) [273, 1920, 1920, 1921], sonepiprazole (pK<sub>i</sub> 8.9) [1892], loxapine (pK<sub>i</sub> 8.1) [1920]</td><td>–</td></tr><tr><td>Sub/family-selective antagonists</td><td>haloperidol (pK<sub>i</sub> 7.5–8.6) [628, 1939, 2006, 2133]</td><td>haloperidol (pK<sub>i</sub> 8.7–8.8) [1191, 1939, 2133]</td><td>SCH-23390 (pK<sub>i</sub> 7.5–9.5) [2060], SKF-83566 (pK<sub>i</sub> 9.4) [2060], ecopipam (pK<sub>i</sub> 8.3) [2060]</td></tr><tr><td>Selective antagonists</td><td>S33084 (pK<sub>i</sub> 9.6) [1450], nafadotride (pK<sub>i</sub> 9.5) [1877], PG01037 (pK<sub>i</sub> 9.2) [756], NGB 2904 (pK<sub>i</sub> 8.8) [2343], SB 277011-A (pK<sub>i</sub> 8) [1783], (+)-S-14297 (pK<sub>i</sub> 6.9–7.9) [1448, 1453]</td><td>L745870 (pK<sub>i</sub> 9.4) [1171], A-381393 (pK<sub>i</sub> 8.8) [1543], L741742 (pK<sub>i</sub> 8.5) [1831], ML398 (pK<sub>i</sub> 7.4) [154]</td><td>–</td></tr><tr><td>Selective allosteric modulators</td><td>SB269652 (Negative) (pK<sub>i</sub> ~9) [642]</td><td>–</td><td>–</td></tr><tr><td>Labelled ligands</td><td>[<sup>3</sup>H]spiperone (Antagonist) (pK<sub>d</sub> 9.9) [888, 2433] – Rat, [<sup>3</sup>H]7-OH-DPAT (Agonist) [1798], [<sup>3</sup>H]PD128907 (Agonist) [29]</td><td>[<sup>125</sup>I]L750667 (Antagonist) (pK<sub>d</sub> 9.8) [1665], [<sup>3</sup>H]NGD941 (Antagonist) (pK<sub>d</sub> 8.3) [1736]</td><td>[<sup>125</sup>I]SCH23982 (Antagonist) (pK<sub>d</sub> 9.1)</td></tr></tbody></table>

**Comments:** The selectivity of many of these agents is less than two orders of magnitude. [<sup>3</sup>H]raclopride exhibits similar high affinity for D<sub>2</sub> and D<sub>3</sub> receptors (low affinity for D<sub>4</sub>), but has been used to label D<sub>2</sub> receptors in the presence of a D<sub>3</sub>-selective antago-

nist. [<sup>3</sup>H]7-OH-DPAT has similar affinity for D<sub>2</sub> and D<sub>3</sub> receptors, but labels only D<sub>3</sub> receptors in the absence of divalent cations. The pharmacological profile of the D<sub>5</sub> receptor is similar to, yet distinct from, that of the D<sub>1</sub> receptor. The splice variants of the

D<sub>2</sub> receptor are commonly termed D<sub>2S</sub> and D<sub>2L</sub> (short and long). The DRD4 gene encoding the D<sub>4</sub> receptor is highly polymorphic in humans, with allelic variations of the protein from amino acid 387 to 515.
Further reading on Dopamine receptors

Beaulieu JM *et al.* (2015) Dopamine receptors - IUPHAR Review 13. *Br. J. Pharmacol.* **172**: 1-23 [PMID:25671228]

Beaulieu JM *et al.* (2011) The physiology, signaling, and pharmacology of dopamine receptors. *Pharmacol. Rev.* **63**: 182-217 [PMID:21303898]

Cumming P. (2011) Absolute abundances and affinity states of dopamine receptors in mammalian brain: A review. *Synapse* **65**: 892-909 [PMID:21308799]

Maggio R *et al.* (2010) Dopamine D2-D3 receptor heteromers: pharmacological properties and therapeutic significance. *Curr Opin Pharmacol* **10**: 100-7 [PMID:19896900]

Ptácek R *et al.* (2011) Dopamine D4 receptor gene DRD4 and its association with psychiatric disorders. *Med. Sci. Monit.* **17**: RA215-20 [PMID:21873960]

Schwartz J-C *et al.*. (1998) Dopamine Receptors. *In The IUPHAR Compendium of Receptor Characterization and Classification* Edited by Girdlestone D: IUPHAR Media: 141-151

Undieh AS. (2010) Pharmacology of signaling induced by dopamine D(1)-like receptor activation. *Pharmacol. Ther.* **128**: 37-60 [PMID:20547182]

Endothelin receptors

G protein-coupled receptors → Endothelin receptors

**Overview:** Endothelin receptors (nomenclature as agreed by the **NC-IUPHAR** Subcommittee on Endothelin Receptors [454]) are activated by the endogenous 21 amino-acid peptides endothelins 1-3 (endothelin-1 (EDN1, P05305), endothelin-2 (EDN2, P20800) and endothelin-3 (EDN3, P14138)).

<table><tr><td>Nomenclature</td><td>ET<sub>A</sub> receptor</td><td>ET<sub>B</sub> receptor</td></tr><tr><td>HGNC, UniProt</td><td>EDNRA, P25101</td><td>EDNRB, P24530</td></tr><tr><td>Potency order of endogenous ligands</td><td>endothelin-1 (EDN1, P05305) = endothelin-2 (EDN2, P20800) &gt; endothelin-3 (EDN3, P14138) [1353]</td><td>endothelin-1 (EDN1, P05305) = endothelin-2 (EDN2, P20800), endothelin-3 (EDN3, P14138) [1854]</td></tr><tr><td>Selective agonists</td><td>–</td><td>sarafotoxin S6c [1163, 1838], BQ 3020 [1793], [Ala<sup>1,3,11,15</sup>ET-1] [1471], IRL 1620 [2268]</td></tr><tr><td>Antagonists</td><td>SB209670 (pK<sub>B</sub> 9.4) [553] – Rat, TAK 044 (pA<sub>2</sub> 8.4) [2271] – Rat, bosentan (pA<sub>2</sub> 7.2) [403] – Rat</td><td>SB209670 (pK<sub>B</sub> 9.4) [553] – Rat, TAK 044 (pA<sub>2</sub> 8.4) [2271] – Rat, bosentan (pK<sub>i</sub> 7.1) [1527]</td></tr><tr><td>Selective antagonists</td><td>macitentan (pIc<sub>50</sub> 9.3) [192], sitaxsentan (pA<sub>2</sub> 8) [2334], FR139317 (Inverse agonist) (pIc<sub>50</sub> 7.3–7.9) [1353], BQ123 (pA<sub>2</sub> 6.9–7.4) [1353], ambrisentan (pA<sub>2</sub> 7.1) [193]</td><td>K-8794 (pIc<sub>50</sub> 8.2) [1951], A192621 (pK<sub>d</sub> 8.1) [2226], BQ788 (pK<sub>d</sub> 7.9–8) [1838], IRL 2500 (pK<sub>d</sub> 7.2) [1838], Ro 46-8443 (pIc<sub>50</sub> 7.2) [232]</td></tr><tr><td>Labelled ligands</td><td>[<sup>125</sup>I]PD164333 (Antagonist) (pK<sub>d</sub> 9.6–9.8) [457], [<sup>3</sup>H]S0139 (Antagonist) (pK<sub>d</sub> 9.2), [<sup>125</sup>I]PD151242 (Antagonist) (pK<sub>d</sub> 9–9.1) [458], [<sup>3</sup>H]BQ123 (Antagonist) (pK<sub>d</sub> 8.5) [944]</td><td>[<sup>125</sup>I]IRL1620 (Agonist) [1544], [<sup>125</sup>I]BQ3020 (Agonist) [810, 1471, 1693], [<sup>125</sup>I][Ala<sup>1,3,11,15</sup>ET-1 (Agonist) [1471]</td></tr></table>

**Comments:** Splice variants of the ET<sub>A</sub> receptor have been identified in rat pituitary cells; one of these, ET<sub>A</sub>R-C13, appeared to show loss of function with comparable plasma membrane expression to wild type receptor [822]. Subtypes of the ET<sub>B</sub> receptor have been proposed, although gene disruption studies in mice suggest that only a single gene product exists [1465]. Crystal structures of the ET<sub>B</sub> receptor bound to the antagonist bosentan and ET<sub>B</sub> selective analogue K-8794 [1951] and selective ET<sub>B</sub> agonists endothelin-3 (EDN3, P14138) and IRL 1620 [1950] have been reported.
Further reading on Endothelin receptors

Clozel M *et al.* (2013) Endothelin receptor antagonists. *Handb Exp Pharmacol* **218**: 199-227 [PMID:24092342]

Davenport AP. (2002) International Union of Pharmacology. XXIX. Update on endothelin receptor nomenclature. *Pharmacol. Rev.* **54**: 219-26 [PMID:12037137]

Davenport AP *et al.* (2016) Endothelin. *Pharmacol. Rev.* **68**: 357-418 [PMID:26956245]

Davenport AP *et al.* (2018) New drugs and emerging therapeutic targets in the endothelin signaling pathway and prospects for personalized precision medicine. *Physiol Res* **67**: S37-S54 [PMID:29947527]

Maguire JJ *et al.* (2014) Endothelin@25 - new agonists, antagonists, inhibitors and emerging research frontiers: IUPHAR Review 12. *Br. J. Pharmacol.* **171**: 5555-72 [PMID:25131455]

G protein-coupled estrogen receptor

G protein-coupled receptors → G protein-coupled estrogen receptor

**Overview:** The G protein-coupled estrogen receptor (GPER, **nomenclature as agreed by the NC-IUPHAR Subcommittee on the G protein-coupled estrogen receptor [1740]**)) was identified following observations of estrogen-evoked cyclic AMP signalling in breast cancer cells [71], which mirrored the differential expression of an orphan 7-transmembrane recep-

tor GPR30 [304]. There are observations of both cell-surface and intracellular expression of the GPER receptor [1789, 2123]. Selective agonist/ antagonists for GPER have been characterized [1740]. Antagonists of the nuclear estrogen receptor, such as **fulvestrant** [596], **tamoxifen** [1789, 2123] and **raloxifene** [1700], as well as the flavonoid 'phytoestrogens' **genistein** and **quercetin** [1352], are

agonists of GPER. A complete review of GPER pharmacology has been recently published [1740]. The roles of GPER in physiological systems throughout the body (cardiovascular, metabolic, endocrine, immune, reproductive) and in cancer have also been reviewed [595, 1203, 1437, 1740, 1741].

Nomenclature

GPER

HGNC, UniProt

GPER1, Q99527

Agonists

fulvestrant [2123], raloxifene [1700], 4-hydroxytamoxifen [1789]

Selective agonists

G-1 [195]

Selective antagonists

G36 (pIC50 6.8–6.9) [485], G15 (pIC50 6.7) [484]

Labelled ligands

[³H]17β-estradiol (Agonist) [2123]

**Comments:** Antagonists at the nuclear estrogen receptor, such as **fulvestrant**, **tamoxifen** [596] and **raloxifene** [1700], as well as the flavonoid 'phytoestrogens' **genistein** and **quercetin** [1352], are agonists at GPER receptors. A complete review of GPER pharmacology has been recently published [1740].

Further reading on G protein-coupled estrogen receptor

Barton M *et al.* (2018) Twenty years of the G protein-coupled estrogen receptor GPER: Historical and personal perspectives. *J. Steroid Biochem. Mol. Biol.* **176**: 4-15 [PMID:28347854]

Gaudet HM *et al.* (2015) The G-protein coupled estrogen receptor, GPER: The inside and inside-out story. *Mol. Cell. Endocrinol.* **418 Pt 3**: 207-19 [PMID:26190834]

Prossnitz ER *et al.* (2015) International Union of Basic and Clinical Pharmacology. XCVII. G Protein-Coupled Estrogen Receptor and Its Pharmacologic Modulators. *Pharmacol. Rev.* **67**: 505-40 [PMID:26023144]

Prossnitz ER *et al.* (2015) What have we learned about GPER function in physiology and disease from knockout mice? *J. Steroid Biochem. Mol. Biol.* **153**: 114-26 [PMID:26189910]
# Formylpeptide receptors

G protein-coupled receptors → Formylpeptide receptors

**Overview:** The formylpeptide receptors (nomenclature agreed by the **NC-IUPHAR Subcommittee on the formylpeptide receptor family [2387]**)) respond to exogenous ligands such as the bacterial product fMet-Leu-Phe (fMLP) and endogenous ligands such as annexin I (ANXA1, P04083), cathepsin G (CTSG, P08311), amyloid β42, serum amyloid A and spinorphin, derived from β-haemoglobin (HBB, P68871).

<table><thead><tr><th></th><th></th><th></th><th></th></tr></thead><tbody><tr><td>Nomenclature</td><td>FPR1</td><td>FPR2/ALX</td><td>FPR3</td></tr><tr><td>HGNC, UniProt</td><td>FPR1, P21462</td><td>FPR2, P25090</td><td>FPR3, P25089</td></tr><tr><td>Potency order of endogenous ligands</td><td>fMet-Leu-Phe > cathepsin G (CTSG, P08311) > annexin I (ANXA1, P04083) [1224, 2058]</td><td>LXA<sub>4</sub> = aspirin triggered lipoxin A4 = ATLa2 = resolvin D1 > LTC<sub>4</sub> = LTD<sub>4</sub> &gt;&gt; 15-deoxy-LXA4 &gt;&gt; fMet-Leu-Phe [401, 600, 602, 750, 2086]</td><td>-</td></tr><tr><td>Endogenous agonists</td><td>-</td><td>LXA<sub>4</sub> [1153], resolvin D1 [1153], aspirin-triggered resolvin D1 [1152], aspirin triggered lipoxin A4</td><td>F2L (HEBP1, Q9NRV9) [1447]</td></tr><tr><td>Agonists</td><td>fMet-Leu-Phe [630, 1963]</td><td>-</td><td>-</td></tr><tr><td>Selective agonists</td><td>-</td><td>ATLa2 [765]</td><td>-</td></tr><tr><td>Endogenous antagonists</td><td>spinorphin (pIC<sub>50</sub> 4.3) [1275, 1526]</td><td>-</td><td>-</td></tr><tr><td>Antagonists</td><td>t-Boc-FLFLF (pK<sub>i</sub> 6–6.5) [2288]</td><td>-</td><td>-</td></tr><tr><td>Selective antagonists</td><td>cyclosporin H (pK<sub>i</sub> 6.1–7.1) [2288, 2370]</td><td>WRWWWWW (pIC<sub>50</sub> 6.6) [92], t-Boc-FLFLF (pIC<sub>50</sub> 4.3–6) [629, 2030, 2245]</td><td>-</td></tr><tr><td>Labelled ligands</td><td>[<sup>3</sup>H]fMet-Leu-Phe (Agonist) [1137]</td><td>[<sup>3</sup>H]LXA<sub>4</sub> (Agonist) [600, 601]</td><td>-</td></tr><tr><td>Comments</td><td>A FITC-conjugated fMLP analogue has been used for binding to the mouse recombinant receptor [833].</td><td>-</td><td>-</td></tr></tbody></table>

**Comments:** Note that the data for FPR2/ALX are also reproduced on the leukotriene receptor page.

## Further reading on Formylpeptide receptors

Dorward DA et al. (2015) The Role of Formylated Peptides and Formyl Peptide Receptor 1 in Governing Neutrophil Function during Acute Inflammation. Am. J. Pathol. **185**: 1172-1184 [PMID:25791526]

Dufton N et al. (2010) Therapeutic anti-inflammatory potential of formyl-peptide receptor agonists. Pharmacol. Ther. **127**: 175-88 [PMID:20546777]

Liu M et al. (2012) G protein-coupled receptor FPR1 as a pharmacologic target in inflammation and human glioblastoma. Int. Immunopharmacol. **14**: 283-8 [PMID:22863814]

Rabiet MJ et al. (2011) N-formyl peptide receptor 3 (FPR3) departs from the homologous FPR2/ALX receptor with regard to the major processes governing chemoattractant receptor regulation, expression at the cell surface, and phosphorylation. J. Biol. Chem. **286**: 26718-31 [PMID:21543323]

Yazid S et al. (2012) Anti-inflammatory drugs, eicosanoids and the annexin A1/FPR2 anti-inflammatory system. Prostaglandins Other Lipid Mediat. **98**: 94-100 [PMID:22123264]

Ye RD et al. (2009) International Union of Basic and Clinical Pharmacology. LXXIII. Nomenclature for the formyl peptide receptor (FPR) family. Pharmacol. Rev. **61**: 119-61 [PMID:19498085]
# Free fatty acid receptors

G protein-coupled receptors → Free fatty acid receptors

**Overview:** Free fatty acid receptors (FFA, **nomenclature as agreed by the NC-IUPHAR Subcommittee on free fatty acid receptors** [455, 2039]) are activated by free fatty acids. Long-chain saturated and unsaturated fatty acids (including C14:0

(myristic acid), C16:0 (palmitic acid), C18:1 (oleic acid), C18:2 (linoleic acid), C18:3, (α-linolenic acid), C20:4 (arachidonic acid), C20:5,n-3 (EPA) and C22:6,n-3 (docosahexaenoic acid)) activate FFA1 [239, 958, 1144] and FFA4 receptors [876, 938, 1617], while

short chain fatty acids (C2 (acetic acid), C3 (propanoic acid), C4 (butyric acid) and C5 (pentanoic acid)) activate FFA2 [249, 1223, 1591] and FFA3 [249, 1223] receptors. The crystal structure for agonist bound FFA1 has been described [2023].

Nomenclature FFA1 receptor

HGNC, UniProt FFAR1, O14842

Endogenous agonists docosahexaenoic acid [239, 958], α-linolenic acid [239, 958, 1144], oleic acid [239, 958, 1144], myristic acid [239, 958, 1144]

Selective agonists AMG-837 [1286], compound 4 [381], TUG-770 [380], TUG-905 [379], GW9508 (Partial agonist) [238], fasiglifam [1028, 1558, 2023, 2157]

Selective antagonists GW1100 (pIC₅₀ 6) [238, 2038]

Comments A wide range of both saturated and unsaturated fatty acids containing from 6 to 22 carbons have been shown to act as agonists at FFA1 [239, 958, 1144]. Antagonist GW1100 is also an oxytocin receptor antagonist [238]. Fasiglifam, TUG-770 and GW9508 are approximately 100 fold selective for FFA1 over FFA4 [238, 380, 1558]. AMG-837 and the related analogue AM6331 have been suggested to have an allosteric mechanism of action at FFA1, with respect to the orthosteric fatty acid binding site [1286, 2353].

FFA2 receptor

FFAR2, O15552

propanoic acid [249, 1223, 1591, 1894], acetic acid [249, 1223, 1591, 1894], butyric acid [249, 1223, 1591, 1894], trans-2-methylcrotonic acid [1894], 1-methylcyclopropanecarboxylic acid [1894]

TUG-1375 [801]

GLPG0974 (pIC₅₀ 8.1) [1546, 1715], CATPB (pIC₅₀ 6.5) [927]

-
<table><tr><td>Nomenclature</td><td>FFA3 receptor</td><td>FFA4 receptor</td><td>GPR42</td></tr><tr><td>HGNC, UniProt</td><td>FFAR3, O14843</td><td>FFAR4, Q5NUL3</td><td>GPR42, O15529</td></tr><tr><td>Endogenous agonists</td><td>propanoic acid [249, 1223, 1894, 2352], butyric acid [249, 1223, 1894, 2352], 1-methylcyclopropanecarboxylic acid [1894]</td><td>α-linolenic acid [1955], myristic acid [2275], α-linolenic acid [2100] – Rat, oleic acid [2275]</td><td>–</td></tr><tr><td>Agonists</td><td>acetic acid [249, 1223, 1894, 2352]</td><td>–</td><td>–</td></tr><tr><td>Selective agonists</td><td>–</td><td>compound A [1616], TUG-891 [1955], NCG21 [2065]</td><td>–</td></tr><tr><td>Comments</td><td>Beta-hydroxybutyrate has been reported to antagonise FFA3 responses to short chain fatty acids [1095]. A range of FFA3 selective molecules with agonist and antagonist properties, but which bind at sites distinct from the short chain fatty acid binding site (i.e. allosteric modulators), have been described [196, 926, 1337].</td><td>A wide range of both saturated and unsaturated fatty acids containing from 6 to 22 carbons have been shown to act as agonists at FFA4 [382] with a small subset listed above. Compound A [PMID 24997608] exhibits more than 1000 fold selectivity [1616], and TUG-891 50-1000 fold selectivity for FFA4 over FFA1 [1955], dependent on the assay. NGC21 exhibits approximately 15 fold selectivity for FFA4 over FFA1 [2057].</td><td>–</td></tr></table>

**Comments:** Short (361 amino acids) and long (377 amino acids) splice variants of human FFA4 have been reported [1490], which differ by a 16 amino acid insertion in intracellular loop 3, and exhibit differences in intracellular signalling properties in recom-

binant systems [2275]. The long FFA4 splice variant has not been identified in other primates or rodents to date [876, 1490].

GPR42 was originally described as a pseudogene within the family (ENSFM00250000002583), but the discovery of several polymor-

phisms suggests that some versions of GPR42 may be functional [1276]. GPR84 is a structurally-unrelated G protein-coupled receptor which has been found to respond to medium chain fatty acids [2254].

Further reading on Free fatty acid receptors

Bolognini D et al. (2016) The Pharmacology and Function of Receptors for Short-Chain Fatty Acids. Mol. Pharmacol. 89: 388-98 [PMID:26719580]

Mancini AD et al. (2013) The fatty acid receptor FFA1/GPR40 a decade later: how much do we know? Trends Endocrinol. Metab. 24: 398-407 [PMID:23631851]

Milligan G et al. (2017) Complex Pharmacology of Free Fatty Acid Receptors. Chem. Rev. 117: 67-110 [PMID:27299848]

Moniri NH. (2016) Free-fatty acid receptor-4 (GPR120): Cellular and molecular function and its role in metabolic disorders. Biochem. Pharmacol. 110-111: 1-15 [PMID:26827942]

Stoddart LA et al. (2008) International Union of Pharmacology. LXXI. Free fatty acid receptors FFA1, -2, and -3: pharmacology and pathophysiological functions. Pharmacol. Rev. 60: 405-17 [PMID:19047536]

Watterson KR et al. (2014) Treatment of type 2 diabetes by free Fatty Acid receptor agonists. Front Endocrinol (Lausanne) 5: 137 [PMID:25221541]
# GABA<sub>B</sub> receptors

G protein-coupled receptors → GABA<sub>B</sub> receptors

**Overview:** Functional GABA<sub>B</sub> receptors (nomenclature as agreed by the NC-IUPHAR Subcommittee on GABA<sub>B</sub> receptors [215, 1710]) are formed from the heterodimerization of two similar 7TM subunits termed GABA<sub>B1</sub> and GABA<sub>B2</sub> [215, 557, 1709, 1710, 2173]. GABA<sub>B</sub> receptors are widespread in the CNS and regulate both pre- and postsynaptic activity. The GABA<sub>B1</sub> subunit, when expressed alone, binds both antagonists and agonists, but the affinity of the latter is generally 10-100-fold less than for the native receptor. Co-expression of GABA<sub>B1</sub> and GABA<sub>B2</sub> subunits allows transport of GABA<sub>B1</sub> to the cell surface and generates a functional receptor that can couple to signal transduction pathways such as high-voltage-activated Ca<sup>2+</sup> channels (Ca<sub>v</sub>2.1, Ca<sub>v</sub>2.2), or inwardly rectifying potassium channels (Kir3) [159, 215, 216]. The GABA<sub>B1</sub> subunit harbours the GABA (orthosteric)-binding site within an extracellular domain (ECD) venus flytrap module (VTM), whereas the GABA<sub>B2</sub> subunit mediates G protein-coupled signalling [215, 681, 683, 1709]. The two

subunits interact by direct allosteric coupling [1485], such that GABA<sub>B2</sub> increases the affinity of GABA<sub>B1</sub> for agonists and reciprocally GABA<sub>B1</sub> facilitates the coupling of GABA<sub>B2</sub> to G proteins [681, 1161, 1709]. GABA<sub>B1</sub> and GABA<sub>B2</sub> subunits assemble in a 1:1 stoichiometry by means of a coiled-coil interaction between α-helices within their carboxy-termini that masks an endoplasmic reticulum retention motif (RXRR) within the GABA<sub>B1</sub> subunit but other domains of the proteins also contribute to their heteromerization [159, 270, 1709]. Recent evidence indicates that higher order assemblies of GABA<sub>B</sub> receptor comprising dimers of heterodimers occur in recombinant expression systems and *in vivo* and that such complexes exhibit negative functional cooperativity between heterodimers [409, 1708]. Adding further complexity, KCTD (potassium channel tetramerization proteins) 8, 12, 12b and 16 associate as tetramers with the carboxy terminus of the GABA<sub>B2</sub> subunit to impart altered signalling kinetics and agonist potency to the receptor complex [116, 1907, 2160] and are re-

viewed by [1711]. The molecular complexity of GABAB receptors is further increased through association with trafficking and effector proteins [Schwenk et al., 2016, Nature Neuroscience 19(2): 233-42] and reviewed by [1707]. Four isoforms of the human GABA<sub>B1</sub> subunit have been cloned. The predominant GABA<sub>B1a</sub> and GABA<sub>B1b</sub> isoforms, which are most prevalent in neonatal and adult brain tissue respectively, differ in their ECD sequences as a result of the use of alternative transcription initiation sites. GABA<sub>B1a</sub>-containing heterodimers localise to distal axons and mediate inhibition of glutamate release in the CA3-CA1 terminals, and GABA release onto the layer 5 pyramidal neurons, whereas GABA<sub>B1b</sub>-containing receptors occur within dendritic spines and mediate slow postsynaptic inhibition [1749, 2216]. Only the 1a and 1b variants are identified as components of native receptors [215]. Additional GABA<sub>B1</sub> subunit isoforms have been described in rodents and humans [1236] and reviewed by [159].

<table><tr><td>Nomenclature</td><td>GABA<sub>B</sub> receptor</td></tr><tr><td>Subunits</td><td>GABA<sub>B1</sub>, GABA<sub>B2</sub>, kctd12b (Accessory protein), KCTD16 (Accessory protein), KCTD12 (Accessory protein), KCTD8 (Accessory protein)</td></tr><tr><td>Agonists</td><td>CGP 44532 [635] – Rat, (-)-baclofen [635] – Rat, 3-APPA [881], baclofen [881, 2327], 3-APMPA [2327]</td></tr><tr><td>Antagonists</td><td>CGP 62349 (pK<sub>i</sub> 8.5–8.9) [881, 2327], CGP 55845 (pK<sub>i</sub> 7.8) [2327], SCH 50911 (pK<sub>i</sub> 5.5–6) [881, 2327], CGP 35348 (pK<sub>i</sub> 4.4) [2327], 2-hydroxy-saclofen (pIC<sub>50</sub> 4.1) [1052] – Rat</td></tr><tr><td>Allosteric modulators</td><td>rac-BHFF (Positive) (pEC<sub>50</sub> 6.6) [1366], GS39783 (Positive) (pK<sub>B</sub> 4.7) [849, 2182], compound 14 (Negative) (pIC<sub>50</sub> 4.4) [351], CGP7930 (Positive) [2181]</td></tr><tr><td>Labelled ligands</td><td>[<sup>3</sup>H]CGP 54626 (Antagonist) (pK<sub>i</sub> 9.1) [1015] – Rat, [<sup>3</sup>H]CGP 62349 (Antagonist) (pK<sub>d</sub> 9.1) [1060] – Rat, [<sup>125</sup>I]CGP 64213 (Antagonist) (pK<sub>d</sub> 9) [650] – Rat, [<sup>125</sup>I]CGP 71872 (Antagonist) (pK<sub>d</sub> 9) [1052] – Rat, [<sup>3</sup>H](R)-(-)-baclofen (Agonist)</td></tr></table>

## Subunits

<table><tr><td>Nomenclature</td><td>GABA<sub>B1</sub></td><td>GABA<sub>B2</sub></td></tr><tr><td>HGNC, UniProt</td><td>GABBR1, Q9UBS5</td><td>GABBR2, O75899</td></tr></table>