**Comments:** Potencies of agonists and antagonists listed in the table, quantified as IC₅₀ values for the inhibition of [³H]CGP27492 binding to rat cerebral cortex membranes, are from [215, 634, 635]. Radioligand K_D values relate to binding to rat brain membranes. CGP 71872 is a photoaffinity ligand for the GABA<sub>B1</sub> subunit [137]. CGP27492 (3-APPA), CGP35024 (3-APMPA) and CGP 44532 act as antagonists at human GABA<sub>A</sub> ρ1 receptors, with potencies in the low micromolar range [634]. In addition to the ligands listed in the table, Ca²⁺ binds to the VTM of the GABA<sub>B1</sub>

subunit to act as a positive allosteric modulator of GABA [650]. Synthetic positive allosteric modulators with low, or no, intrinsic activity include CGP7930, GS39783, BHF-177 [2223] and (+)-BHFF [9, 159, 166, 634]. The site of action of CGP7930 and GS39783 appears to be on the heptahelical domain of the GABA<sub>B2</sub> subunit [534, 1709]. In the presence of CGP7930 or GS39783, CGP 35348 and 2-hydroxy-saclofen behave as partial agonists [634]. A negative allosteric modulator of GABA<sub>B</sub> activity has been reported [351]. Knock-out of the GABA<sub>B1</sub> subunit in C57B mice causes

the development of severe tonic-clonic convulsions that prove fatal within a month of birth, whereas GABA<sub>B1</sub><sup>-/-</sup> BALB/c mice, although also displaying spontaneous epileptiform activity, are visible. The phenotype of the latter animals additionally includes hyperalgesia, hyperlocomotion (in a novel, but not familiar, environment), hyperdopaminergia, memory impairment and behaviours indicative of anxiety [563, 2184]. A similar phenotype has been found for GABA<sub>B2</sub><sup>-/-</sup> BALB/c mice [669].

**Further reading on GABA<sub>B</sub> receptors**

Bowery NG *et al*. (2002) International Union of Pharmacology. XXXIII. Mammalian gamma-aminobutyricacid(B) receptors: structure and function. *Pharmacol Rev.* **54**: 247-264 [PMID:12037141]

Froestl W. (2011) An historical perspective on GABAergic drugs. *Future Med Chem* **3**: 163-75 [PMID:21428811]

Gassmann M *et al*. (2012) Regulation of neuronal GABA(B) receptor functions by subunit composition. *Nat. Rev. Neurosci.* **13**: 380-94 [PMID:22595784]

Pin JP *et al*. (2016) Organization and functions of mGlu and GABAB receptor complexes. *Nature* **540**: 60-68 [PMID:27905440]
# Galanin receptors

G protein-coupled receptors → Galanin receptors

**Overview:** Galanin receptors (provisional nomenclature as recommended by NC-IUPHAR [612]) are activated by the endogenous peptides galanin (GAL, P22466) and galanin-like peptide (GALP, Q9UBC7). Human galanin (GAL,

P22466) is a 30 amino-acid non-amidated peptide [579]; in other species, it is 29 amino acids long and C-terminally amidated. Amino acids 1–14 of galanin are highly conserved in mammals, birds, reptiles, amphibia and fish. Shorter peptide species (e.g.

human galanin-1–19 [155] and porcine galanin-5–29 [1970]) and N-terminally extended forms (e.g. N-terminally seven and nine residue elongated forms of porcine galanin [156, 1970]) have been reported.

<table><tr><td>Nomenclature</td><td>GAL<sub>1</sub> receptor</td><td>GAL<sub>2</sub> receptor</td><td>GAL<sub>3</sub> receptor</td></tr><tr><td>HGNC, UniProt</td><td>GALR1, P47211</td><td>GALR2, O43603</td><td>GALR3, O60755</td></tr><tr><td>Potency order of endogenous ligands</td><td>galanin (GAL, P22466) > galanin-like peptide (GALP, Q9UBC7) [1623]</td><td>galanin-like peptide (GALP, Q9UBC7) ≥ galanin (GAL, P22466) [1623]</td><td>galanin-like peptide (GALP, Q9UBC7) > galanin (GAL, P22466) [1197]</td></tr><tr><td>Agonists</td><td>–</td><td>galanin(2-29) (rat/mouse) [1651, 2257, 2258, 2259] – Rat</td><td>–</td></tr><tr><td>Selective agonists</td><td>–</td><td>[D-Trp<sup>2</sup>]galanin-(1-29) [1996] – Rat</td><td>–</td></tr><tr><td>Selective antagonists</td><td>2,3-dihydro-1,4-dithien-1,1,4,4-tetroxide (pIC<sub>50</sub> 5.6) [1914]</td><td>M871 (pK<sub>i</sub> 7.9) [2010]</td><td>SNAP 398299 (pK<sub>i</sub> 8.3) [1132, 1133, 2069], SNAP 37889 (pK<sub>i</sub> 7.8–7.8) [1132, 1133, 2069]</td></tr><tr><td>Selective allosteric modulators</td><td>–</td><td>CYM2503 (Positive) (pEC<sub>50</sub> 9.2) [1322] – Rat</td><td>–</td></tr><tr><td>Labelled ligands</td><td>[125I][Tyr<sup>26</sup>]galanin (human) (Agonist) [608], [125I][Tyr<sup>26</sup>]galanin (human) (Agonist) [608]</td><td>[125I][Tyr<sup>26</sup>]galanin (human) (Agonist) [2258] – Rat</td><td>[125I][Tyr<sup>26</sup>]galanin (pig) (Agonist) [207, 1997]</td></tr><tr><td>Comments</td><td>–</td><td>The CYM2503 PAM potentiates the anticonvulsant activity of endogenous galanin in mouse seizure models [1322].</td><td>–</td></tr></table>

**Comments:** Galanin-(1-11) is a high-affinity agonist at GAL<sub>1</sub>/GAL<sub>2</sub> (pK<sub>i</sub> 9), and galanin(2-11) is selective for GAL<sub>2</sub> and GAL<sub>3</sub> compared with GAL<sub>1</sub> [1321]. [125I]-[Tyr<sup>26</sup>]galanin binds to all three subtypes with K<sub>d</sub> values generally reported to range from 0.05 to 1 nM, depending on the assay conditions used [608, 1982, 1996, 1997, 2258]. Porcine galanin-(3-29) does not bind to cloned GAL<sub>1</sub>, GAL<sub>2</sub> or GAL<sub>3</sub> receptors, but a receptor that is functionally activated by porcine galanin-(3–29) has been reported in pituitary

and gastric smooth muscle cells [758, 2342]. Additional galanin receptor subtypes are also suggested from studies with chimeric peptides (e.g. M15, M35 and M40), which act as antagonists in functional assays in the cardiovascular system [2171], spinal cord [2307], locus coeruleus, hippocampus [114] and hypothalamus [115, 1249], but exhibit agonist activity at some peripheral sites [115, 758]. The chimeric peptides M15, M32, M35, M40 and C7 are agonists at GAL<sub>1</sub> receptors expressed endogenously in Bowes

human melanoma cells [1623], and at heterologously expressed recombinant GAL<sub>1</sub>, GAL<sub>2</sub> and GAL<sub>3</sub> receptors [608, 1996, 1997]. Recent studies have described the synthesis of a series of novel, systemically-active, galanin analogues, with modest preferential binding at the GAL<sub>2</sub> receptor. Specific chemical modifications to the galanin backbone increased brain levels of these peptides after i.v. injection and several of these peptides exerted a potent antidepressant-like effect in mouse models of depression [1847].

## Further reading on Galanin receptors

* Foord SM et al. (2005) International Union of Pharmacology. XLVI. G protein-coupled receptor list. *Pharmacol Rev* **57**: 279-288 [PMID:15914470]

* Lang R et al. (2015) Physiology, signaling, and pharmacology of galanin peptides and receptors: three decades of emerging diversity. *Pharmacol. Rev.* **67**: 118-75 [PMID:25428932]

* Lang R et al. (2011) The galanin peptide family in inflammation. *Neuropeptides* **45**: 1-8 [PMID:21087790]

* Lawrence C et al. (2011) Galanin-like peptide (GALP) is a hypothalamic regulator of energy homeostasis and reproduction. *Front Neuroendocrinol* **32**: 1-9 [PMID:20558195]

* Webling KE et al. (2012) Galanin receptors and ligands. *Front Endocrinol* (Lausanne) **3**: 146 [PMID:23233848]
# Ghrelin receptor

G protein-coupled receptors → Ghrelin receptor

**Overview:** The ghrelin receptor (nomenclature as agreed by the **NC-IUPHAR Subcommittee for the Ghrelin receptor** [456]) is activated by a 28 amino-acid peptide originally isolated from rat stomach, where it is cleaved from a 117 amino-acid precursor (GHRL, Q9UBU3). The human gene encoding the precursor peptide has 83% sequence homology to rat preproghrelin, although the mature peptides from rat and human differ by only two amino acids [1399]. Alternative splicing results

in the formation of a second peptide, [des-Gln¹⁴]ghrelin (GHRL, Q9UBU3) with equipotent biological activity [907]. A unique post-translational modification (octanoylation of Ser³, catalysed by ghrelin O-acyltransferase (MBOAT4, Q96T53) [2374] occurs in both peptides, essential for full activity in binding to ghrelin receptors in the hypothalamus and pituitary, and for the release of growth hormone from the pituitary [1128]. Structure activity studies showed the first five N-terminal amino acids to be

the minimum required for binding [131], and receptor mutagenesis has indicated overlap of the ghrelin binding site with those for small molecule agonists and allosteric modulators of ghrelin (GHRL, Q9UBU3) function [899]. In cell systems, the ghrelin receptor is constitutively active [900], but this is abolished by a naturally occurring mutation (A204E) that results in decreased cell surface receptor expression and is associated with familial short stature [1652].

<table><tr><td>Nomenclature</td><td>ghrelin receptor</td></tr><tr><td>HGNC, UniProt</td><td>GHSR, Q92847</td></tr><tr><td>Potency order of endogenous ligands</td><td>ghrelin (GHRL, Q9UBU3) = [des-Gln<sup>14</sup>]ghrelin (GHRL, Q9UBU3) [130, 1399]</td></tr><tr><td>Antagonists</td><td>liver enriched antimicrobial peptide 2 (LEAP2, Q969E1) (pIC<sub>50</sub> 8.2) [675]</td></tr><tr><td>Selective antagonists</td><td>GSK1614343 (pIC<sub>50</sub> 8.4) [1848], GSK1614343 (pK<sub>B</sub> 8) [1684] – Rat</td></tr><tr><td>Labelled ligands</td><td>[<sup>125</sup>I][His<sup>9</sup>]ghrelin (human) (Agonist) [1051], [<sup>125</sup>I][Tyr<sup>4</sup>]ghrelin (human) (Agonist) [1515]</td></tr></table>

**Comments:** [des-octanoyl]ghrelin (GHRL, Q9UBU3) has been shown to bind (as [<sup>125</sup>I]Tyr⁴-des-octanoyl-ghrelin) and have effects in the cardiovascular system [130], which raises the possible existence of different receptor subtypes in peripheral tissues and the central nervous system. A potent inverse agonist has been

identified ([D-Arg¹, D-Phe⁵, D-Trp⁷,⁹, Leu¹¹]substance P, pD₂ 8.3; [897]). Ulimorelin, described as a ghrelin receptor agonist (pKᵢ 7.8 and pD₂ 7.5 at human recombinant ghrelin receptors), has been shown to stimulate ghrelin receptor mediated food intake and gastric emptying but not elicit release of growth hormone, or modify ghrelin stimulated growth hormone release, thus pharmacologically

discriminating the orexigenic and gastrointestinal actions of ghrelin (GHRL, Q9UBU3) from the release of growth hormone [622]. A number of selective antagonists have been reported, including peptidomimetic [1514] and non-peptide small molecules including GSK1614343 [1684, 1848].

## Further reading on Ghrelin receptor

* Andrews ZB. (2011) The extra-hypothalamic actions of ghrelin on neuronal function. *Trends Neurosci.* **34**: 31-40 [PMID:21035199]

* Angelidis G et al. (2010) Current and potential roles of ghrelin in clinical practice. *J. Endocrinol. Invest.* **33**: 823-38 [PMID:21293171]

* Briggs DI et al. (2011) Metabolic status regulates ghrelin function on energy homeostasis. *Neuroendocrinology* **93**: 48-57 [PMID:21124019]

* Callaghan B et al. (2014) Novel and conventional receptors for ghrelin, desacyl-ghrelin, and pharmacologically related compounds. *Pharmacol. Rev.* **66**: 984-1001 [PMID:25107984]

* Davenport AP et al. (2005) International Union of Pharmacology. LVI. Ghrelin receptor nomenclature, distribution, and function. *Pharmacol. Rev.* **57**: 541-6 [PMID:16382107]
# Glucagon receptor family

G protein-coupled receptors → Glucagon receptor family

**Overview:** The glucagon family of receptors (nomenclature as agreed by the **NC-IUPHAR Subcommittee on the Glucagon receptor family** [1410]) are activated by the endogenous peptide (27-44 aa) hormones glucagon (GCG, P01275), glucagon-like peptide 1 (GCG, P01275), glucagon-like peptide 2

(GCG, P01275), glucose-dependent insulinotropic polypeptide (also known as gastric inhibitory polypeptide (GIP, P09681)), GHRH (GHRH, P01286) and secretin (SCT, P09683). One common precursor (GCG) generates glucagon (GCG, P01275), glucagon-like peptide 1 (GCG, P01275) and

glucagon-like peptide 2 (GCG, P01275) peptides [952]. For a recent review on the current understanding of the structures of GLP-1 and GLP-1R, the molecular basis of their interaction, and the signaling events associated with it, see de Graaf et al., 2016 [736].

<table><tr><td>Nomenclature</td><td>GHRH receptor</td><td>GIP receptor</td><td>GLP-1 receptor</td></tr><tr><td>HGNC, UniProt</td><td>GHRHR, Q02643</td><td>GIPR, P48546</td><td>GLP1R, P43220</td></tr><tr><td>Endogenous agonists</td><td>GHRH (GHRH, P01286)</td><td>gastric inhibitory polypeptide (GIP, P09681) [2225]</td><td>glucagon-like peptide 1-(7-36) amide (GCG, P01275) [1020], glucagon-like peptide 1-(7-37) (GCG, P01275) [498]</td></tr><tr><td>Agonists</td><td>JL-38 [289], sermorelin</td><td>–</td><td>liraglutide [11199], lixisenatide [2290], WB4-24 [583]</td></tr><tr><td>Selective agonists</td><td>BIM28011 [431], tesamorelin</td><td>–</td><td>semaglutide [1206], exendin-4 [1460], exendin-4 [1020], exendin-3 (P20394) [1776]</td></tr><tr><td>Selective antagonists</td><td>JV-1-36 (pK<sub>i</sub> 10.1–10.4) [1886, 2205, 2206] – Rat, JV-1-38 (pK<sub>i</sub> 10.1) [1886, 2205, 2206] – Rat</td><td>[Pro<sup>3</sup>]GIP [672] – Mouse</td><td>exendin-(9-39) (pK<sub>i</sub> 8.1) [1020], GLP-1-(9-36) (pIC<sub>50</sub> 6.9) [1486] – Rat, T-0632 (pIC<sub>50</sub> 4.7) [2131]</td></tr><tr><td>Labelled ligands</td><td>[<sup>125</sup>I]GHRH (human) (Agonist) [212] – Rat</td><td>[<sup>125</sup>I]GIP (human) (Agonist) [648] – Rat</td><td>[<sup>125</sup>I]GLP-1-(7-36)-amide (Agonist) [1020], [<sup>125</sup>I]exendin-(9-39) (Antagonist) (pK<sub>d</sub> 8.3) [1020], [<sup>125</sup>I]GLP-1-(7-37) (human) (Agonist)</td></tr></table>

<table><tr><td>Nomenclature</td><td>GLP-2 receptor</td><td>glucagon receptor</td><td>secretin receptor</td></tr><tr><td>HGNC, UniProt</td><td>GLP2R, O95838</td><td>GCGR, P47871</td><td>SCTR, P47872</td></tr><tr><td>Endogenous agonists</td><td>glucagon-like peptide 2 (GCG, P01275) [2128]</td><td>glucagon (GCG, P01275) [1718]</td><td>secretin (SCT, P09683) [376]</td></tr><tr><td>Agonists</td><td>teduglutide [1423]</td><td>NNC1702 [2418]</td><td>–</td></tr><tr><td>Selective antagonists</td><td>–</td><td>L-168,049 (pIC<sub>50</sub> 8.4) [312], adomeglivant (pK<sub>i</sub> 8.2) [1059, 1063], des-His<sup>1</sup>-[Glu<sup>9</sup>]glucagon-NH<sub>2</sub> (pA<sub>2</sub> 7.2) [2176, 2177] – Rat, NNC 92-1687 (pK<sub>i</sub> 5) [1345], BAY27-9955 [1695]</td><td>[[(CH<sub>2</sub>NH)<sup>4,5</sup>]secretin (pK<sub>i</sub> 5.3) [776]</td></tr><tr><td>Labelled ligands</td><td>–</td><td>[<sup>125</sup>I]glucagon (human, mouse, rat) (Agonist)</td><td>[<sup>125</sup>I](Tyr<sup>10</sup>)secretin-27 (rat) (Agonist) [2172] – Rat</td></tr></table>

**Comments:** The glucagon receptor has been reported to interact with receptor activity modifying proteins (RAMPs), specifically RAMP2, in heterologous expression systems [384], although the physiological significance of this has yet to be established.
Further reading on Glucagon receptor family

Ahrén B. (2019) Glucagon-like peptide-1 receptor agonists for type 2 diabetes: A rational drug development. *J Diabetes Investig* **10**: 196-201 [PMID:30099845]

Andersen A et al. (2018) Glucagon-like peptide 1 in health and disease. *Nat Rev Endocrinol* **14**: 390-403 [PMID:29728598]

Gentilella R et al. (2019) Glucagon-like peptide-1 receptor agonists in type 2 diabetes treatment: are they all the same? *Diabetes Metab. Res. Rev.* **35**: e3070 [PMID:30156747]

Graaf Cd et al. (2016) Glucagon-Like Peptide-1 and Its Class B G Protein-Coupled Receptors: A Long March to Therapeutic Successes. *Pharmacol. Rev.* **68**: 954-1013 [PMID:27630114]

Romera I et al. (2019) A Review of Practical Issues on the Use of Glucagon-Like Peptide-1 Receptor Agonists for the Management of Type 2 Diabetes. *Diabetes Ther* **10**: 5-19 [PMID:30506340]

Trujillo JM et al. (2014) GLP-1 receptor agonists for type 2 diabetes mellitus: recent developments and emerging agents. *Pharmacotherapy* **34**: 1174-86 [PMID:25382096]

Zhang Y et al. (2017) Cryo-EM structure of the activated GLP-1 receptor in complex with a G protein. *Nature* **546**: 248-253 [PMID:28538729]

Glycoprotein hormone receptors

G protein-coupled receptors → Glycoprotein hormone receptors

**Overview:** Glycoprotein hormone receptors (provisional nomenclature [612]) are activated by a non-covalent heterodimeric glycoprotein made up of a common α chain (glycoprotein hormone common alpha subunit (CGA, P01215)

CGA, P01215), with a unique β chain that confers the biological specificity to FSH (CGA FSHB, P01215 P01225), LH (CGA LHB, P01215 P01229), hCG (CGA CGB3, P01215 P01233) or TSH (CGA TSHB, P01215 P01222). There is binding cross-reactivity across

the endogenous agonists for each of the glycoprotein hormone receptors. The deglycosylated hormones appear to exhibit reduced efficacy at these receptors [1850].

Nomenclature FSH receptor

HGNC, UniProt FSHR, P23945

Potency order of endogenous ligands FSH (CGA FSHB, P01215 P01225)

Labelled ligands [¹²⁵I]FSH (human) (Agonist)

LH receptor

LHCGR, P22888

LH (CGA LHB, P01215 P01229), hCG (CGA CGB3, P01215 P01233) [997, 1534]

[¹²⁵I]LH (Agonist),

[¹²⁵I]chorionic gonadotropin (human) (Agonist)

TSH receptor

TSHR, P16473

TSH (CGA TSHB, P01215 P01222)

[¹²⁵I]TSH (human) (Agonist)

Further reading on Glycoprotein hormone receptors

Jiang X et al. (2012) Structure of follicle-stimulating hormone in complex with the entire ectodomain of its receptor. *Proc. Natl. Acad. Sci. U.S.A.* **109**: 12491-6 [PMID:22802634]

Kleinau G et al. TSH receptor mutations and disease. *Thyroid Disease Manager*. Accessed on 2017-02-23.

Tao YX et al. (2009) Follicle stimulating hormone receptor mutations and reproductive disorders. *Prog Mol Biol Transl Sci* **89**: 115-31 [PMID:20374735]

Troppmann B et al. (2013) Structural and functional plasticity of the luteinizing hormone/choriogonadotrophin receptor. *Hum. Reprod. Update* **19**: 583-602 [PMID:23686864]
# Gonadotrophin-releasing hormone receptors

G protein-coupled receptors → Gonadotrophin-releasing hormone receptors

**Overview:** GnRH₁ and GnRH₂ receptors (provisional nomenclature [612], also called Type I and Type II GnRH receptor, respectively [1456]) have been cloned from numerous species, most of which express two or three types of GnRH receptor [1455, 1456, 1971]. GnRH I (GNRH1, P01148) (p-Glu-His-Trp-Ser-Tyr-Gly-Leu-Arg-Pro-Gly-NH2) is a hypothalamic decapeptide also known as luteinizing hormone-releasing hormone, gonadoliberin, luliberin, gonadorelin or simply as GnRH. It is a member of a family of similar peptides found in many species [1455, 1456, 1971] including GnRH II (GNRH2, O43555) (pGlu-His-Trp-Ser-His-Gly-Trp-Tyr-

Pro-Gly-NH₂ (which is also known as chicken GnRH-II). Receptors for three forms of GnRH exist in some species but only GnRH I and GnRH II and their cognate receptors have been found in mammals [1455, 1456, 1971]. GnRH₁ receptors are expressed by pituitary gonadotrophs, where they mediate the effects of GnRH on gonadotropin hormone synthesis and secretion that underpin central control of mammalian reproduction. GnRH analogues are used in assisted reproduction and to treat steroid hormone-dependent conditions [1079]. Notably, agonists cause desensitization of GnRH-stimulated gonadotropin secretion and the con-

sequent reduction in circulating sex steroids is exploited to treat hormone-dependent cancers of the breast, ovary and prostate [1079]. GnRH1 receptors are selectively activated by GnRH I and all lack the COOH-terminal tails found in other GPCRs. GnRH₂ receptors do have COOH-terminal tails and (where tested) are selective for GnRH II over GnRH I. GnRH2 receptors are expressed by some primates but not by humans [1496]. Phylogenetic classifications divide GnRH receptors into three [1456] or five groups [2311] and highlight examples of gene loss through evolution, with humans retaining only one ancient gene.

<table><tr><td>Nomenclature</td><td>GnRH₁ receptor</td><td>GnRH₂ receptor</td></tr><tr><td>HGNC, UniProt</td><td>GNRHR, P30968</td><td>GNRHR2, Q96P88</td></tr><tr><td>Potency order of endogenous ligands</td><td>GnRH I (GNRH1, P01148) &gt; GnRH II (GNRH2, O43555) [1456]</td><td>GnRH II (GNRH2, O43555) &gt; GnRH I (GNRH1, P01148) (Monkey) [1454]</td></tr><tr><td>Endogenous agonists</td><td>GnRH I (GNRH1, P01148) [1323], GnRH II (GNRH2, O43555) [606, 1323, 2032]</td><td>GnRH II (GNRH2, O43555) [1454] – Monkey, GnRH I (GNRH1, P01148) [1454, 1456] – Monkey</td></tr><tr><td>Selective agonists</td><td>buserelin [1555], buserelin [1554], buserelin [1554], triptorelin [127], leuprolide [2045], goserelin, histrelin, nafarelin</td><td>–</td></tr><tr><td>Antagonists</td><td>iturelix (pK<sub>i</sub> 9.5) [1811]</td><td>–</td></tr><tr><td>Selective antagonists</td><td>cetrorelix (pK<sub>i</sub> 9.3–10) [128, 129, 2045], abarelix (pK<sub>i</sub> 9.1–9.5) [2045], degarelix (pK<sub>i</sub> 8.8) [2194], ganirelix</td><td>trptorelix-1 [1357] – Monkey</td></tr><tr><td>Labelled ligands</td><td>[125I]cetrorelix (Antagonist) (pK<sub>d</sub> 9.7) [892], [125I]triptorelin (Agonist) [480] – Rat, [125I]buserelin (Agonist) [1178] – Rat, [125I]GnRH I (human, mouse, rat) (Agonist)</td><td>–</td></tr></table>

**Comments:** GnRH₁ and GnRH₂ receptors couple primarily to G<sub>q/11</sub> [752] but coupling to G<sub>s</sub> and G<sub>i</sub> is evident in some systems [1157, 1178]. GnRH₂ receptors may also mediate (heterotrimeric) G protein-independent signalling to protein kinases [319]. There is increasing evidence for expression of GnRH receptors on hormone-dependent cancer cells where they can exert antiproliferative and/or proapoptotic effects and mediate effects of cytotoxins conjugated to GnRH analogues [357, 814, 1284, 1885]. In some human cancer cell models GnRH II (GNRH2, O43555) is more potent than GnRH I (GNRH1, P01148), implying mediation by GnRH₂ receptors [757], but GnRH₂ receptors are not expressed

by humans because the human GNRHR2 gene contains a frame shift and internal stop codon [1496]. The possibility remains that this gene generates GnRH₂ receptor-related proteins (other than the full-length receptor) that mediate responses to GnRH II (GNRH2, O43555) (see [1560]). Alternatively, evidence for multiple active GnRH receptor conformations [319, 320, 597, 1407, 1456] raises the possibility that GnRH₁ receptor-mediated proliferation inhibition in hormone-dependent cancer cells is dependent upon a conformation that couples to G<sub>i</sub> rather than G<sub>q/11</sub> proteins as in pituitary cells [320, 1407]. Loss-of-function mutations in the GnRH₁ receptor and deficiency of GnRH I (GNRH1, P01148) are

associated with hypogonadotropic hypogonadism although some 'loss of function' mutations may actually prevent trafficking of 'functional' GnRH₁ receptors to the cell surface, as evidenced by recovery of function by nonpeptide antagonists [1230]. Human GnRH₁ receptors are poorly expressed at the cell surface because of failure to meet structural quality control criteria for endoplasmic reticulum exit [598, 1232], and this increases susceptibility to point mutations that further impair trafficking [598, 1230]. GnRH receptor signalling may require receptor oligomerisation [412, 1155].
Further reading on Gonadotrophin-releasing hormone receptors

Desaulniers AT et al. (2017) Expression and Role of Gonadotropin-Releasing Hormone 2 and Its Receptor in Mammals. *Front Endocrinol (Lausanne)* **8**: 269 [PMID:29312140]

Limonta P et al. (2012) GnRH receptors in cancer: from cell biology to novel targeted therapeutic strategies. *Endocr. Rev.* **33**: 784-811 [PMID:22778172]

McArdle CA and Roberson MS.. (2015) Gonadotropes and gonadotropin-releasing hormone signaling. *In Knobil and Neill's Physiology of Reproduction (4th edition)*. Edited by Plant TM and Zeleznik AJ.: Elsevier Inc.: [ISBN: 9780123971753]

Millar RP et al. (2004) Gonadotropin-releasing hormone receptors. *Endocr Rev* **25**: 235-275 [PMID:15082521]

Tao YX et al. (2014) Chaperoning G protein-coupled receptors: from cell biology to therapeutics. *Endocr. Rev.* **35**: 602-47 [PMID:24661201]

GPR18, GPR55 and GPR119

G protein-coupled receptors → GPR18, GPR55 and GPR119

**Overview:** GPR18, GPR55 and GPR119 (provisional nomenclature), although showing little structural similarity to CB₁ and CB₂ cannabinoid receptors, respond to endogenous agents analogous to the endogenous cannabinoid ligands, as well as some natural/synthetic cannabinoid receptor ligands [1692]. Although there are multiple reports to indicate that GPR18, GPR55 and GPR119 can be activated *in vitro* by N-arachidonylglYCine, lysophosphatidylinositol and N-oleoylethanolamide, respectively, there is a lack of evidence for activation by these lipid messengers *in vivo*. As such, therefore, these receptors retain their orphan status.

<table><tr><td>Nomenclature</td><td>GPR18</td><td>GPR55</td><td>GPR119</td></tr><tr><td>HGNC, UniProt</td><td>GPR18, Q14330</td><td>GPR55, Q9Y2T6</td><td>GPR119, Q8TDV5</td></tr><tr><td>Potency order of endogenous ligands</td><td>-</td><td>-</td><td>N-oleoylethanolamide, N-palmitoylethanolamine &gt; SEA (anandamide is ineffective) [1643]</td></tr><tr><td>Endogenous agonists</td><td>N-arachidonylglYCine [1126]</td><td>lysophosphatidylinositol [852, 1625, 2015], 2-arachidonylglycerolphosphoinositol [1627]</td><td>N-oleoylethanolamide [389, 1643, 2015], N-palmitoylethanolamine, SEA</td></tr><tr><td>Selective agonists</td><td>-</td><td>AM251 [852, 1042, 1843]</td><td>AS1269574 [2400], PSN632408 [1643], PSN375963 [1643]</td></tr><tr><td>Selective antagonists</td><td>-</td><td>CID16020046 (apparent pA<sub>2</sub> (pA<sub>2</sub> 7.3) [1044], ML193 (pIC<sub>50</sub> 6.7) [865]</td><td>-</td></tr><tr><td>Comments</td><td>The pairing of N-arachidonylglYCine with GPR18 was not replicated in two studies based on arrestin assays [2015, 2389]. See [455] for discussion.</td><td>See reviews [455] and [1961].</td><td>In addition to those shown above, further small molecule agonists have been reported [793].</td></tr></table>

**Comments:** GPR18 failed to respond to a variety of lipid-derived agents in an *in vitro* screen [2389], but has been reported to be activated by Δ⁹-tetrahydrocannabinol [1422]. GPR55 responds to AM251 and rimonabant at micromolar concentrations, compared to their nanomolar affinity as CB₁ receptor

antagonists/inverse agonists [1692]. It has been reported that lysophosphatidylinositol acts at other sites in addition to GPR55 [2367]. N-Arachidonylserine has been suggested to act as a low efficacy agonist/antagonist at GPR18 *in vitro* [1420]. It has also been suggested oleoyl-lysophosphatidylcholine acts, at least

in part, through GPR119 [1592]. Although PSN375963 and PSN632408 produce GPR119-dependent responses in heterologous expression systems, comparison with N-oleoylethanolamide-mediated responses suggests additional mechanisms of action [1592].
Further reading on GPR18, GPR55 and GPR119

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. *Pharma-col. Rev.* **65**: 967-86 [PMID:23686350]

Hassing HA *et al*. (2016) Biased signaling of lipids and allosteric actions of synthetic molecules for GPR119. *Biochem. Pharmacol.* **119**: 66-75 [PMID:27569424]

Irving A *et al*. (2017) Cannabinoid Receptor-Related Orphan G Protein-Coupled Receptors. *Adv Pharmacol* **80**: 223-247 [PMID:28826536]

Liu B *et al*. (2015) GPR55: from orphan to metabolic regulator? *Pharmacol. Ther.* **145**: 35-42 [PMID:24972076]

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]

Histamine receptors

G protein-coupled receptors → Histamine receptors

**Overview:** Histamine receptors (nomenclature as agreed by the NC-IUPHAR Subcommittee on Histamine Receptors [871, 1653]) are activated by the endogenous ligand histamine. Marked species differences exist between histamine receptor orthologues [871]. The human and rat H₃ receptor genes are subject to significant splice variance [100]. The potency order of his-

tamine at histamine receptor subtypes is H₃ = H₄ > H₂ > H₁ [1653]. Some agonists at the human H₃ receptor display significant ligand bias [1803]. Antagonists of all 4 histamine receptors have clinical uses: H₁ antagonists for allergies (e.g. cetirizine), H₂ antagonists for acid-reflux diseases (e.g. ranitidine), H₃ antagonists for narcolepsy (e.g. pitolisant/WAKIX; Registered) and

H₄ antagonists for atopic dermatitis (e.g. ZPL-3893787; Phase IIa) [1653] and vestibular neuritis (AUV) (SENS-111 (Seliforant, previously UR-63325), entered and completed vestibular neuritis (AUV) Phase IIa efficacy and safety trials, respectively) [75, 2213].

Nomenclature H₁ receptor

HGNC, UniProt HRH1, P35367

Selective agonists methylhistaprodifen [1923], histaprodifen [1283]

Antagonists cyproheptadine (pKᵢ 10.2) [1469], promethazine (pKᵢ 9.6) [697], mepyramine (Inverse agonist) (pKᵢ 8.7–9) [204, 1775], cetirizine (Inverse agonist) (pKᵢ 8.2) [1469], diphenhydramine (pKᵢ 7.9) [204]

Selective antagonists clemastine (pKᵢ 10.3) [79], desloratadine (pKᵢ 9) [1266], triprolidine (pKᵢ 8.5–9) [204, 1469], azelastine (pKᵢ 8.9) [1738], astemizole (pKᵢ 8.5) [1673]

Labelled ligands [³H]pyrilamine (Antagonist, Inverse agonist) (pK₉ 8.4–9.1) [464, 1469, 1901, 1923], [¹¹C]doxepin (Antagonist) (pK₉ 9) [955], [¹¹C]pyrilamine (Antagonist, Inverse agonist)

H₂ receptor

HRH2, P25021

amthamine [1149]

tiotidine (pKᵢ 7.5) [161] – Rat, ranitidine (pKᵢ 7.1) [1262], cimetidine (pKᵢ 6.8) [299]

[¹²⁵I]iodoaminopotentidine (Antagonist) (pK₉ 8.7) [1185] – Rat, [³H]tiotidine (Antagonist) (pK₉ 7.7–8.7) [1480]
<table><tr><td>Nomenclature</td><td>H<sub>3</sub> receptor</td><td>H<sub>4</sub> receptor</td></tr><tr><td>HGNC, UniProt</td><td>HRH3, Q9Y5N1</td><td>HRH4, Q9H3N8</td></tr><tr><td>Selective agonists</td><td>immethridine [1110], methimepip [1109], MK-0249 (Inverse agonist) [1536]</td><td>clobenpropit (Partial agonist) [570, 1283, 1298, 1299, 1509], 4-methylhistamine [674, 1283], ST-1006 [1653], VUF 8430 [1282]</td></tr><tr><td>Antagonists</td><td>iodophenpropit (pK<sub>i</sub> 8.2–8.7) [2305, 2338]</td><td>–</td></tr><tr><td>Selective antagonists</td><td>pitolisant (pK<sub>i</sub> 8.1–8.6) [1653, 2447], A331440 (pK<sub>i</sub> 8.5) [794], conessine (pK<sub>i</sub> 8.3) [1653], MK-0249 (pK<sub>i</sub> 8.2) [1653], thioperamide (Selective for H<sub>3</sub>/H<sub>4</sub> compared to H<sub>1</sub> and H<sub>3</sub>.) (pK<sub>i</sub> 7.1–7.7) [404, 569, 570, 1280, 1320, 2305, 2338], ciproxifan (pK<sub>i</sub> 6.7–7.3) [404, 569, 570, 1280, 1653, 2338]</td><td>ZPL-3893787 (pK<sub>i</sub> 8.3) [1653], INCB-38579 (pK<sub>i</sub> 8.3) [1653], JNJ 7777120 (pK<sub>i</sub> 7.8–8.3) [1283, 2001, 2129], JNJ-39758979 (pK<sub>i</sub> 7.9) [1653, 1878], thioperamide (Selective for H<sub>3</sub>/H<sub>4</sub> compared to H<sub>1</sub> and H<sub>3</sub>.) (pK<sub>i</sub> 6.3–7.6) [569, 570, 1298, 1299, 1509, 2441]</td></tr><tr><td>Labelled ligands</td><td>[123I]iodoproxyfan (Antagonist) (pK<sub>d</sub> 10.2) [1280], [125I]iodophenpropit (Antagonist) (pK<sub>d</sub> 9.2) [980] – Rat, [3H](R)-α-methylhistamine (Agonist) [1298], N-[3H]α-methylhistamine (Agonist) [349] – Mouse</td><td>[3H]JNJ 7777120 (Antagonist) (pK<sub>d</sub> 8.4) [2129]</td></tr></table>

**Comments:** Histaprodifen and methylhistaprodifen are reduced efficacy agonists. The H<sub>4</sub> receptor appears to exhibit broadly similar pharmacology to the H<sub>3</sub> receptor for imidazole-containing ligands, although (R)-α-methylhistamine and N-α-methylhistamine

are less potent, while clobenpropit acts as a reduced efficacy agonist at the H<sub>4</sub> receptor and an antagonist at the H<sub>3</sub> receptor [1298, 1542, 1579, 1612, 2441]. Moreover, 4-methylhistamine is identified as a high affinity, full agonist for the human H<sub>4</sub> receptor

[1283]. [3H]histamine has been used to label the H<sub>4</sub> receptor in heterologous expression systems.

## Further reading on Histamine receptors

* Gbahou F *et al.* (2012) The histamine autoreceptor is a short isoform of the H<sub>3</sub> receptor. *Br. J. Pharmacol.* **166**: 1860-71 [PMID:22356432]

* Nieto-Alamilla G *et al.* (2016) The Histamine H3 Receptor: Structure, Pharmacology, and Function. *Mol. Pharmacol.* **90**: 649-673 [PMID:27563055]

* Panula P *et al.* (2015) International Union of Basic and Clinical Pharmacology. XCVIII. Histamine Receptors. *Pharmacol. Rev.* **67**: 601-55 [PMID:26084539]

* van Rijn RM *et al.* (2008) Cloning and characterization of dominant negative splice variants of the human histamine H4 receptor. *Biochem. J.* **414**: 121-31 [PMID:18452403]
# Hydroxycarboxylic acid receptors

G protein-coupled receptors → Hydroxycarboxylic acid receptors

**Overview:** The hydroxycarboxylic acid family of receptors (ENSFM00500000271913, **nomenclature as agreed by the NC-IUPHAR Subcommittee on Hydroxycarboxylic acid receptors [455, 1614]**)) respond to organic acids, including the

endogenous hydroxy carboxylic acids 3-hydroxy butyric acid and L-lactic acid, as well as the lipid lowering agents nicotinic acid (niacin), acipimox and acifran [2004, 2159, 2320]. These receptors were provisionally described as nicotinic acid receptors, although

nicotinic acid shows submicromolar potency at HCA₂ receptors only and is unlikely to be the natural ligand [2159, 2320].

<table><tr><td>Nomenclature</td><td>HCA<sub>1</sub> receptor</td><td>HCA<sub>2</sub> receptor</td><td>HCA<sub>3</sub> receptor</td></tr><tr><td>HGNC, UniProt</td><td>HCAR1, Q9BXC0</td><td>HCAR2, Q8TDS4</td><td>HCAR3, P49019</td></tr><tr><td>Potency order of endogenous ligands</td><td>–</td><td>β-D-hydroxybutyric acid > butyric acid</td><td>–</td></tr><tr><td>Endogenous agonists</td><td>L-lactic acid [18, 290, 1300, 2015]</td><td>β-D-hydroxybutyric acid [2077], butyric acid</td><td>3-hydroxyoctanoic acid [17]</td></tr><tr><td>Agonists</td><td>compound 2 [1853], 3,5-dihydroxybenzoic acid [1297]</td><td>SCH 900271 [1646], GSK256073 [2022]</td><td>–</td></tr><tr><td>Selective agonists</td><td>–</td><td>MK 6892 [1946], MK 1903 [180], nicotinic acid [2004, 2159, 2320], acipimox [2004, 2320], monomethyl fumarate [2101]</td><td>compound 60 [1981], IBC 293 [1925]</td></tr><tr><td>Labelled ligands</td><td>–</td><td>[³H]nicotinic acid (Agonist) [2004, 2159, 2320]</td><td>–</td></tr></table>

**Comments:** Further closely-related GPCRs include the 5-oxoeicosanoid receptor (OXER1, Q8TDS5) and GPR31 (O00270). Lactate activates HCA₁ on adipocytes in an autocrine manner. It inhibits lipolysis and thereby promotes anabolic effects. HCA₂

and HCA₃ regulate adipocyte lipolysis and immune functions under conditions of increased FFA formation through lipolysis (e.g., during fasting). HCA₂ agonists acting mainly through the receptor on immune cells exert antiatherogenic and anti-inflammatory

effects. HCA₂ is also a receptor for butyrate and mediates some of the beneficial effects of short-chain fatty acids produced by gut microbiota. HCA₃ has been shown to be activated by aromatic D-amino acids.

## Further reading on Hydroxycarboxylic acid receptors

Boatman PD *et al.* (2008) Nicotinic acid receptor agonists. *J. Med. Chem.* **51**: 7653-62 [PMID:18983141]

Graff EC *et al.* (2016) Anti-inflammatory effects of the hydroxycarboxylic acid receptor 2. *Metab. Clin. Exp.* **65**: 102-13 [PMID:26773933]

Kamanna VS *et al.* (2013) Recent advances in niacin and lipid metabolism. *Curr. Opin. Lipidol.* **24**: 239-45 [PMID:23619367]

Offermanns S. (2017) Hydroxy-Carboxylic Acid Receptor Actions in Metabolism. *Trends Endocrinol. Metab.* **28**: 227-236 [PMID:28087125]

Offermanns S *et al.* (2011) International Union of Basic and Clinical Pharmacology. LXXXII: Nomenclature and Classification of Hydroxy-carboxylic Acid Receptors (GPR81, GPR109A, and GPR109B). *Pharmacol. Rev.* **63**: 269-90 [PMID:21454438]

Offermanns S *et al.* (2015) Nutritional or pharmacological activation of HCA(2) ameliorates neuroinflammation. *Trends Mol Med* **21**: 245-55 [PMID:25766751]
# Kisspeptin receptor

G protein-coupled receptors → Kisspeptin receptor

**Overview:** The kisspeptin receptor (nomenclature as agreed by the NC-IUPHAR Subcommittee on the kisspeptin receptor [1102]), like neuropeptide FF (NPFF), prolactin-releasing peptide (PrP) and QRFP receptors (provisional nomenclature) re-

sponds to endogenous peptides with an arginine-phenylalanine-amide (RFamide) motif. Kisspeptin-54 (KISS1, Q15726) (KP54, originally named metastin), kisspeptin-13 (KISS1, Q15726) (KP13) and kisspeptin-10 (KISS1) (KP10) are biologically-active peptides

cleaved from the KISS1 (Q15726) gene product. Kisspeptins have roles in, for example, cancer metastasis, fertility/puberty regulation and glucose homeostasis.

<table><tr><td>Nomenclature</td><td>kisspeptin receptor</td></tr><tr><td>HGNC, UniProt</td><td>KISS1R, Q969F8</td></tr><tr><td>Endogenous agonists</td><td>kisspeptin-10 (KISS1) [1142, 1624], kisspeptin-54 (KISS1, Q15726) [1142, 1624], kisspeptin-14 (KISS1, Q15726) [1142], kisspeptin-13 (KISS1, Q15726) [1142]</td></tr><tr><td>Selective agonists</td><td>4-fluorobenzoyl-FGLRW-NH2 [2143], [dY]<sup>1</sup>KP-10 [439] – Mouse, TAK-448 [1593]</td></tr><tr><td>Selective antagonists</td><td>peptide 234 [1822]</td></tr><tr><td>Labelled ligands</td><td>[<sup>125</sup>I]Tyr<sup>45</sup>-kisspeptin-15 (Agonist) [1624], [<sup>125</sup>I]kisspeptin-13 (human) (Agonist) [1427], [<sup>125</sup>I]kisspeptin-10 (human) (Agonist) [1142], [<sup>125</sup>I]kisspeptin-14 (human) (Agonist) [1427], [d-Tyr-<sup>14</sup>C]TAK-448 (Agonist) [1502]</td></tr></table>

**Comments:** 2-acylamino-4,6-diphenylpyridine derivatives have been described and are the first small molecule kisspeptin receptor antagonists reported with potential for treatment of sex-hormone dependent diseases such as prostate cancer and endometriosis [1120].

## Further reading on Kisspeptin receptor

* Harter CJL et al. (2018) The role of kisspeptin neurons in reproduction and metabolism. *J. Endocrinol.* **238**: R173-R183 [PMID:30042117]

* Kanda S et al. (2013) Structure, synthesis, and phylogeny of kisspeptin and its receptor. *Adv. Exp. Med. Biol.* **784**: 9-26 [PMID:23550000]

* Kirby HR et al. (2010) International Union of Basic and Clinical Pharmacology. LXXVII. Kisspeptin receptor nomenclature, distribution, and function. *Pharmacol. Rev.* **62**: 565-78 [PMID:21079036]

* Oakley AE et al. (2009) Kisspeptin signaling in the brain. *Endocr. Rev.* **30**: 713-43 [PMID:19770291]

* Pasquier J et al. (2014) Molecular evolution of GPCRs: Kisspeptin/kisspeptin receptors. *J. Mol. Endocrinol.* **52**: T101-17 [PMID:24577719]
# Leukotriene receptors

G protein-coupled receptors → Leukotriene receptors

**Overview:** The leukotriene receptors (nomenclature as agreed by the NC-IUPHAR subcommittee on Leukotriene Receptors [279, 280]) are activated by the endogenous ligands leukotrienes (LT), synthesized from lipoxygenase metabolism of arachidonic acid. The human BLT₁ receptor is the high affinity LTB₄ receptor whereas the BLT₂ receptor in addition to being a low-affinity LTB₄ receptor also binds several other lipoxygenase-products, such as 12S-HETE, 12S-HPETE, 15S-HETE, and the thromboxane synthase product

12-hydroxyheptadecatrienoic acid. The BLT receptors mediate chemotaxis and immunomodulation in several leukocyte populations and are in addition expressed on non-myeloid cells, such as vascular smooth muscle and endothelial cells. In addition to BLT receptors, LTB₄ has been reported to bind to the peroxisome proliferator activated receptor (PPAR) α [1288] and the vanilloid TRPV1 ligand-gated nonselective cation channel [1421]. The receptors for the cysteinyl-leukotrienes (i.e. LTC₄, LTD₄ and LTE₄) are termed CysLT₁ and CysLT₂ and exhibit distinct expression pat-

terns in human tissues, mediating for example smooth muscle cell contraction, regulation of vascular permeability, and leukocyte activation. There is also evidence in the literature for additional CysLT receptor subtypes, derived from functional in vitro studies, radioligand binding and in mice lacking both CysLT₁ and CysLT₂ receptors [280]. Cysteinyl-leukotrienes have also been suggested to signal through the P2Y₁₂ receptor [625, 1600, 1659], GPR17 [395] and GPR99 [1036].

<table><thead><tr><th></th><th>BLT<sub>1</sub> receptor</th><th>BLT<sub>2</sub> receptor</th><th>CysLT<sub>1</sub> receptor</th><th>CysLT<sub>2</sub> receptor</th><th>OXE receptor</th><th>FPR2/ALX</th></tr></thead><tbody><tr><td>Nomenclature</td><td>BLT<sub>1</sub> receptor</td><td>BLT<sub>2</sub> receptor</td><td>CYSLTR<sub>1</sub>, Q9Y271</td><td>CYSLTR<sub>2</sub>, Q9NS75</td><td>OXER<sub>1</sub>, Q8TD55</td><td>FPR2, P25090</td></tr><tr><td>HGNC, UniProt</td><td>LTB4R, Q15722</td><td>LTB4R2, Q9NPC1</td><td>LTD<sub>4</sub> &gt; LTC<sub>4</sub> &gt; LTE<sub>4</sub> [1333, 1867]</td><td>LTC<sub>4</sub> ≥ LTD<sub>4</sub> &gt; LTE<sub>4</sub> [844, 1604, 2087]</td><td>5-oxo-ETE, 5-oxo-C20:3, 5-oxo-ODE &gt; 5-oxo-15-HETE &gt; 5S-HPETE &gt; 5S-HETE [739, 908, 1013, 1607, 1664, 1729, 1908]</td><td>LXA<sub>4</sub> = aspirin triggered lipoxin A4 = ATLa2 = resolvin D1 &gt; LTC<sub>4</sub> = LTD<sub>4</sub> &gt; 15-deoxy-LXA4 &gt; fMet-Leu-Phe [401, 600, 602, 750, 2086]</td></tr><tr><td>Potency order of endogenous ligands</td><td>LTB<sub>4</sub> &gt; 20-hydroxy-LTB<sub>4</sub> &gt; 12R-HETE [2395]</td><td>12-hydroxyheptadecatrienoic acid &gt; LTB<sub>4</sub> &gt; 12S-HETE = 12S-HPETE &gt; 15S-HETE &gt; 12R-HETE &gt; 20-hydroxy-LTB<sub>4</sub> [1633, 2395]</td><td>LTD<sub>4</sub> &gt; LTC<sub>4</sub> &gt; LTE<sub>4</sub> [1333, 1867]</td><td>LTC<sub>4</sub> ≥ LTD<sub>4</sub> &gt; LTE<sub>4</sub> [844, 1604, 2087]</td><td>5-oxo-12-HETE (pIC<sub>50</sub> 6.3) [1728]</td><td>LXA<sub>4</sub> [1153], resolvin D1 [1153], aspirin-triggered resolvin D1 [1152], aspirin triggered lipoxin A4</td></tr><tr><td>Endogenous agonists</td><td>—</td><td>—</td><td>—</td><td>—</td><td>—</td><td>ATLa2 [765]</td></tr><tr><td>Selective agonists</td><td>—</td><td>—</td><td>—</td><td>—</td><td>—</td><td>ATLa2 [765]</td></tr><tr><td>Endogenous antagonists</td><td>—</td><td>—</td><td>—</td><td>—</td><td>—</td><td>ATLa2 [765]</td></tr><tr><td>Antagonists</td><td>—</td><td>—</td><td>pranlukast (pK<sub>i</sub> 7.1–8.8) [301, 1777], pobilukast (pK<sub>i</sub> 7.1) [303]</td><td>pranlukast (pA<sub>2</sub> 7.1) [302], pobilukast (pA<sub>2</sub> 6.2) [302]</td><td>—</td><td>—</td></tr><tr><td>Selective antagonists</td><td>BIIL 260 (pK<sub>i</sub> 8.8) [168, 536], CP105696 (pIC<sub>50</sub> 8.1) [1964], U75302 (pK<sub>i</sub> 6.4) [189]</td><td>LY255283 (pIC<sub>50</sub> 6–7.1) [859, 2395]</td><td>ICl198615 (pK<sub>i</sub> 9.7) [646] – Guinea pig, zafirlukast (zafirlukast is only about 100-fold selective for CysLT<sub>1</sub>) (pK<sub>i</sub> 8.9) [301, 1777], montelukast (pK<sub>i</sub> 8.6) [1777], MK-571 (pIC<sub>50</sub> 8) [1333]</td><td>BayCysLT<sub>2</sub> (pA<sub>2</sub> 8.4) [306], BayCysLT<sub>2</sub> (pA<sub>2</sub> 8.3) [306], HAMI3379 (pIC<sub>50</sub> 7.4) [2339]</td><td>—</td><td>WRWWWW (pIC<sub>50</sub> 6.6) [92], t-Boc-FLFLF (pIC<sub>50</sub> 4.3–6) [629, 2030, 2245]</td></tr><tr><td>Labelled ligands</td><td>[3H]LTB<sub>4</sub> (Agonist) [2394], [3H]CGS23131 (Antagonist) (pK<sub>d</sub> 7.9) [965]</td><td>[3H]LTB<sub>4</sub> (pK<sub>d</sub> 7.6–9.7)</td><td>[3H]LTD<sub>4</sub> (Agonist), [3H]ICI-198615 (Antagonist) (pK<sub>d</sub> 10.6) [1830]</td><td>[3H]LTD<sub>4</sub> (Agonist) [844]</td><td>[3H]5-oxo-ETE (Agonist) [1607]</td><td>[3H]LXA<sub>4</sub> (Agonist) [600, 601]</td></tr></tbody></table>
**Comments:** The FPR2/ALX receptor (nomenclature as agreed by the **NC-IUPHAR** subcommittee on **Leukotriene and Lipoxin Receptors** [280]) is activated by the endogenous lipid-derived, anti-inflammatory ligands lipoxin A₄ (LXA₄) and 15-epi-LXA₄ (aspirin triggered lipoxin A₄, ATL). The FPR2/ALX receptor also interacts with endogenous peptide and protein ligands, such as MHC binding peptide [365] as well as annexin I (ANXA1, P04083) (ANXA1) and its N-terminal peptides [415, 1688]. In addition, a soluble hydrolytic product of protease action on the urokinase-type plasminogen activator receptor has been reported

to activate the FPR2/ALX receptor [1788]. Furthermore, FPR2/ALX has been suggested to act as a receptor mediating the proinflammatory actions of the acute-phase reactant, serum amyloid A [2002, 2047]. The agonist activity of the lipid mediators described has been questioned [804, 1716], which may derive from batch-to-batch differences, partial agonism or biased agonism. Results from Cooray *et al.* (2013) [415] have addressed this issue and the role of homodimers and heterodimers in intracellular signaling. A receptor selective for LXB₄ has been suggested from functional studies [64, 1343, 1818]. Note that the data for FPR2/ALX are also

reproduced on the [Formylpeptide receptor pages](#).

Oxoeicosanoid receptors (OXE, nomenclature agreed by the **NC-IUPHAR** subcommittee on **Oxoeicosanoid Receptors** [236]) are activated by endogenous chemotactic eicosanoid ligands oxidised at the C-5 position, with 5-oxo-ETE the most potent agonist identified for this receptor. Initial characterization of the heterologously expressed OXE receptor suggested that polyunsaturated fatty acids, such as docosahexaenoic acid and EPA, acted as receptor antagonists [908].

## Further reading on Leukotriene receptors

Brink C *et al.* (2004) International Union of Pharmacology XLIV. Nomenclature for the Oxoeicosanoid Receptor. *Pharmacol. Rev.* **56**: 149-157 [PMID:15001665]

Brink C *et al.* (2003) International Union of Pharmacology XXXVII. Nomenclature for leukotriene and lipoxin receptors. *Pharmacol. Rev.* **55**: 195-227 [PMID:12615958]

Bäck M *et al.* (2011) International Union of Basic and Clinical Pharmacology. LXXXIV: leukotriene receptor nomenclature, distribution, and pathophysiological functions. *Pharmacol. Rev.* **63**: 539-84 [PMID:21771892]

Bäck M *et al.* (2014) Update on leukotriene, lipoxin and oxoeicosanoid receptors: IUPHAR Review **7**. *Br. J. Pharmacol.* **171**: 3551-74 [PMID:24588652]

Laidlaw TM *et al.* (2012) Cysteinyl leukotriene receptors, old and new; implications for asthma. *Clin. Exp. Allergy* **42**: 1313-20 [PMID:22925317]

# Lysophospholipid (LPA) receptors

G protein-coupled receptors → Lysophospholipid (LPA) receptors

**Overview:** Lysophosphatidic acid (LPA) receptors (nomenclature as agreed by the **NC-IUPHAR** Subcommittee on **Lysophospholipid Receptors** [455, 1080]) are activated by the endogenous phospholipid LPA. The first receptor, LPA₁, was identified as ventricular zone gene-1 (vzg-1) [840], leading to deorphanisation of members of the endothelial differentiation gene (edg) family as other LPA receptors along with sphingosine 1-phosphate (S1P) receptors. Additional LPA receptor GPCRs were later identified. Gene names have been codified as LPAR1, etc. to reflect the receptor function of proteins. The crystal structure of LPA₁ was solved and demonstrates extracellular LPA access to the

binding pocket, consistent with proposed delivery *via* autotaxin [378]. These studies have also implicated cross-talk with endocannabinoids *via* phosphorylated intermediates that can also activate these receptors. The identified receptors can account for most, although not all, LPA-induced phenomena in the literature, indicating that a majority of LPA-dependent phenomena are receptor-mediated. Binding affinities of unlabeled, natural LPA and AEAp to LPA₁ were measured using backscattering interferometry ($pK_d$ = 9) [1466]. Binding affinities were 77-fold lower than than values obtained using radioactivity [2371]. Targeted deletion of LPA receptors has clarified signalling pathways and identified

physiological and pathophysiological roles. Independent validation by multiple groups has been reported in the peer-reviewed literature for all six LPA receptors described in the tables, including further validation using a distinct read-out *via* a novel TGFα "shedding" assay [949]. LPA has also been described as an agonist for the transient receptor potential (Trp) ion channel TRPV1 [1586] and TRPA1 [1111]. LPA was originally proposed to be a ligand for GPCR35, but data show that in fact it is a receptor for CXCL17 (CXCL17, Q6UXB2) [1379]. All of these proposed non-GPCR receptor identities require confirmation and are not currently recognized as bona fide LPA receptors.
<table><thead><tr><th></th><th>LPA<sub>1</sub> receptor</th><th>LPA<sub>2</sub> receptor</th><th>LPA<sub>3</sub> receptor</th><th>LPA<sub>4</sub> receptor</th><th>LPA<sub>5</sub> receptor</th><th>LPA<sub>6</sub> receptor</th></tr></thead><tbody><tr><td>Nomenclature</td><td>LPA<sub>1</sub>, Q92633</td><td>LPA<sub>2</sub>, Q9HBW0</td><td>LPA<sub>3</sub>, Q9UBYS</td><td>LPA<sub>4</sub>, Q99677</td><td>LPA<sub>5</sub>, Q9H1C0</td><td>LPA<sub>6</sub>, P43657</td></tr><tr><td>HGNC, UniProt</td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Selective agonists</td><td>–</td><td>dodecylphosphate [2221], decyl dihydrogen phosphate [2221], GRI977143 [1106]</td><td>OMPT [818]</td><td>–</td><td>–</td><td>–</td></tr><tr><td>Antagonists</td><td>Ki16425 (pIC<sub>50</sub> 6.6–6.9) [1622] – Mouse, VPC12249 (pK<sub>i</sub> 5.2–6.9) [846] – Mouse, VPC32179 [839]</td><td>–</td><td>VPC12249 (pK<sub>i</sub> 6.4) [846], VPC32179 [839]</td><td>–</td><td>–</td><td>–</td></tr><tr><td>Sub/family-selective antagonists</td><td>–</td><td>–</td><td>Ki16425 (pK<sub>i</sub> 6.4) [1622]</td><td>–</td><td>–</td><td>–</td></tr><tr><td>Selective antagonists</td><td>BMS-986020 (pIC<sub>50</sub> 8.9), AM966 (pIC<sub>50</sub> 6.7–7.8) [2068], ONO-7300243 (pIC<sub>50</sub> 6.8) [2108], AM095 (pIC<sub>50</sub> 6–6.1) [2068]</td><td>–</td><td>dioctanoylglycerol pyrophosphate (pK<sub>i</sub> 5.5–7) [604, 1622]</td><td>–</td><td>AS2717638 (pIC<sub>50</sub> 7.4) [1521], TCLPA5 (pIC<sub>50</sub> 6.1) [1148]</td><td>–</td></tr></tbody></table>

**Comments:** Ki16425 [1622], VPC12249 [846] and VPC32179 [839] have dual antagonist activity at LPA₁ and LPA₃ receptors. There is growing evidence for *in vivo* efficacy of these chemical

antagonists in several disorders, including fetal hydrocephalus [2408], fetal hypoxia [857], lung fibrosis [1618], systemic sclerosis [1618] and atherosclerosis progression [1154]. The LPA₂

selective agonist, GRI977143, also shows efficacy in an animal model of multiple sclerosis [1896]. The LPA₅ selective antagonist, AS2717638, is effective in pain models [1058].

## Further reading on Lysophospholipid (LPA) receptors

Chun J *et al.* (2010) International Union of Basic and Clinical Pharmacology. LXXVIII. Lysophospholipid receptor nomenclature. *Pharmacol. Rev.* **62**: 579-87 [PMID:21079037]

Kihara Y *et al.* (2014) Lysophospholipid receptor nomenclature review: IUPHAR Review 8. *Br. J. Pharmacol.* **171**: 3575-94 [PMID:24602016]

Yung YC *et al.* (2015) Lysophosphatidic Acid signaling in the nervous system. *Neuron* **85**: 669-82 [PMID:25695267]

# Lysophospholipid (S1P) receptors

G protein-coupled receptors → Lysophospholipid (S1P) receptors

**Overview:** Sphingosine 1-phosphate (S1P) receptors (nomenclature as agreed by the **NC-IUPHAR Subcommittee on Lysophospholipid receptors [1080]**)) are activated by the endogenous lipid sphingosine 1-phosphate (S1P). Originally cloned as orphan members of the endothelial differentiation gene (edg)

family, current gene names have been designated as S1P₁R through S1P₅R [884]. S1PRs, particularly S1P₁, are expressed throughout all mammalian organ systems. Ligand delivery occurs *via* two known carriers (or "chaperones"): albumin and HDL-bound apolipoprotein M (ApoM), the latter of which elicits biased

agonist signaling by S1P₁ in multiple cell types [173, 649]. The five S1PRs, two chaperones, and active cellular metabolism have complicated analyses of receptor ligand binding in native systems. Signaling pathways and physiological roles have been characterized through radioligand binding in heterologous expression sys-
tems, targeted deletion of the different S1PRs, and most recently, mouse models that report *in vivo* S1P1R activation [1134, 1135]. A crystal structure of an S1P₁-T4 fusion protein confirmed aspects of ligand binding, specificity, and receptor activation determined

previously through biochemical and genetic studies [172, 805]. Fingolimod (FTY720), the first drug to target any of the lysophospholipid receptors, binds to four of the five S1PRs, and was the first oral therapy for multiple sclerosis [390]. The mechanisms of

action of fingolimod and other S1PR modulating drugs in development include binding S1PRs in multiple organ systems, e.g., immune and nervous systems, although the precise nature of their receptor interactions requires clarification [405, 753, 754, 1739].

<table><thead><tr><th></th><th>S1P<sub>1</sub> receptor</th><th>S1P<sub>2</sub> receptor</th><th>S1P<sub>3</sub> receptor</th><th>S1P<sub>4</sub> receptor</th><th>S1P<sub>5</sub> receptor</th></tr></thead><tbody><tr><td>Nomenclature</td><td>S1P<sub>1</sub> receptor</td><td>S1P<sub>2</sub> receptor</td><td>S1P<sub>3</sub> receptor</td><td>S1P<sub>4</sub> receptor</td><td>S1P<sub>5</sub> receptor</td></tr><tr><td>HGNC, UniProt</td><td>S1PR1, P21453</td><td>S1PR2, O95136</td><td>S1PR3, Q99500</td><td>S1PR4, O95977</td><td>S1PR5, Q9H228</td></tr><tr><td>Potency order of endogenous ligands</td><td>sphingosine 1-phosphate > dihydrospingosine 1-phosphate [49, 1628]</td><td>sphingosine 1-phosphate > dihydrospingosine 1-phosphate [49, 1628]</td><td>sphingosine 1-phosphate > dihydrospingosine 1-phosphate [1628]</td><td>sphingosine 1-phosphate > dihydrospingosine 1-phosphate [2189]</td><td>sphingosine 1-phosphate > dihydrospingosine 1-phosphate [946]</td></tr><tr><td>Agonists</td><td>tingolimod-phosphate [237, 615], siponimod [709, 1649], etrasimod [275]</td><td>–</td><td>tingolimod-phosphate [237, 615], tingolimod-phosphate [237, 615]</td><td>tingolimod-phosphate [237, 615, 1650, 1864, 2362], etrasimod [274, 275]</td><td>tingolimod-phosphate [237, 615, 1650], siponimod [671, 694, 2178], etrasimod [275]</td></tr><tr><td>Selective agonists</td><td>RP-001 [288], ponesimod [191], cenerimod [1703], CYM5442 [721], SEW2871 [1864] – Mouse</td><td>–</td><td>CYM-5541 [1004]</td><td>CYM-50308 [2179]</td><td>A-971432 [490, 889]</td></tr><tr><td>Antagonists</td><td>VPC23019 (pK<sub>i</sub> 7.9) [460], VPC03090-P (pK<sub>i</sub> 7.6–7.7) [1069], VPC44116 (pIC<sub>50</sub> 7.6) [616]</td><td>–</td><td>VPC44116 (pK<sub>i</sub> 6.5) [616], VPC23019 (pK<sub>i</sub> 5.9) [460]</td><td>–</td><td>–</td></tr><tr><td>Selective antagonists</td><td>NIBR-0213 (pIC<sub>50</sub> 8.6) [1751], W146 (pK<sub>i</sub> 7.1) [1865]</td><td>JTE-013 (pIC<sub>50</sub> 7.8) [1638]</td><td>TY-52156 (pK<sub>i</sub> 7) [1522]</td><td>CYM-50358 (pIC<sub>50</sub> 7.6) [325, 761]</td><td>–</td></tr></tbody></table>

**Comments:** The FDA-approved immunomodulator fingolimod (FTY720) is phosphorylated *in vivo* [33] to generate an agonist with activity at S1P₁, S1P₃, S1P₄ and S1P₅ receptors [237, 1371]. Many of the physiological consequences of fingolimod-phosphate ad-

ministration, as well as those of other currently described S1P₁ agonists, may involve functional antagonism *via* ubiquitination and subsequent degradation of S1P₁ [1637]. Additionally, receptor specificities of the different compounds may depend on the

functional assay system utilized and from which species the receptor sequence originated.

## Further reading on Lysophospholipid (S1P) receptors

*Chew WS et al. (2016) To fingolimod and beyond: The rich pipeline of drug candidates that target S1P signaling. *Pharmacol. Res.* **113**: 521-532 [PMID:27663260]

*Chun J et al. (2010) International Union of Basic and Clinical Pharmacology. LXXVIII. Lysophospholipid receptor nomenclature. *Pharmacol. Rev.* **62**: 579-87 [PMID:21079037]

*Cyster JG et al. (2012) Sphingosine-1-phosphate and lymphocyte egress from lymphoid organs. *Annu. Rev. Immunol.* **30**: 69-94 [PMID:22149932]

*Pyne NJ et al. (2017) Sphingosine 1-Phosphate Receptor 1 Signaling in Mammalian Cells. *Molecules* **22**: [PMID:28241498]

*Rosen H et al. (2013) Sphingosine-1-phosphate and its receptors: structure, signaling, and influence. *Annu. Rev. Biochem.* **82**: 637-62 [PMID:23527695]

*Yanagida K et al. (2017) Vascular and Immunobiology of the Circulatory Sphingosine 1-Phosphate Gradient. *Annu. Rev. Physiol.* **79**: 67-91 [PMID:27813829]
# Melanin-concentrating hormone receptors

G protein-coupled receptors → Melanin-concentrating hormone receptors

**Overview:** Melanin-concentrating hormone (MCH) receptors (**provisional nomenclature as recommended by NC-IUPHAR [612]**)) are activated by an endogenous nonadecameric cyclic peptide identical in humans and rats (DFDMLRCMLGRVYRPCWQV; mammalian MCH) generated from a precursor (*PMCH*, P20382), which also produces neuropeptide EI (*PMCH*, P20382) and neuropeptide GE (*PMCH*, P20382).

<table><tr><td>Nomenclature</td><td>MCH<sub>1</sub> receptor</td><td>MCH<sub>2</sub> receptor</td></tr><tr><td>HGNC, UniProt</td><td>MCHR1, Q99705</td><td>MCHR2, Q969V1</td></tr><tr><td>Selective antagonists</td><td>GW803430 (pIC<sub>50</sub> 9.3) [860], SNAP-7941 (pA<sub>2</sub> 9.2) [206], T-226296 (pIC<sub>50</sub> 8.3) [2093], ATC0175 (pIC<sub>50</sub> 7.9–8.1) [329]</td><td>–</td></tr><tr><td>Labelled ligands</td><td>[<sup>125</sup>I]S36057 (Antagonist) (pK<sub>d</sub> 9.2–9.5) [77], [<sup>125</sup>I][Phe<sup>13</sup>,Tyr<sup>19</sup>]MCH (Agonist) [269], [<sup>3</sup>H]MCH (human, mouse, rat) (Agonist) [269]</td><td>–</td></tr></table>

**Comments:** The MCH₂ receptor appears to be a non-functional pseudogene in rodents [2098].

## Further reading on Melanin-concentrating hormone receptors

Chung S *et al.* (2011) Recent updates on the melanin-concentrating hormone (MCH) and its receptor system: lessons from MCH1R antagonists. *J. Mol. Neurosci.* **43**: 115-21 [PMID:20582487]

Eberle AN *et al.* (2010) Cellular models for the study of the pharmacology and signaling of melanin-concentrating hormone receptors. *J. Recept. Signal Transduct. Res.* **30**: 385-402 [PMID:21083507]

Foord SM *et al.* (2005) International Union of Pharmacology. XLVI. G protein-coupled receptor list. *Pharmacol Rev* **57**: 279-288 [PMID:15914470]

Takase K *et al.* (2014) Meta-analysis of melanin-concentrating hormone signaling-deficient mice on behavioral and metabolic phenotypes. *PLoS ONE* **9**: e99961 [PMID:24924345]
# Melanocortin receptors

G protein-coupled receptors → Melanocortin receptors

**Overview:** Melanocortin receptors (provisional nomenclature as recommended by **NC-IUPHAR** [612]) are activated by members of the melanocortin family (α-MSH (POMC, P01189), β-MSH (POMC, P01189) and γ-MSH (POMC, P01189) forms; δ form is not found in mammals) and adrenocorticotrophin (ACTH (POMC, P01189)). Endogenous antagonists include agouti (ASIP, P42127) and agouti-related protein (AGRP, O00253). ACTH(1-24) was approved by the US FDA as a diagnostic agent for adrenal function test, whilst NDP-MSH was approved by EMA for the treatment of erythropoietic protoporphyria. Several synthetic melanocortin receptor agonists are under clinical development.

<table><thead><tr><th></th><th>MC<sub>1</sub> receptor</th><th>MC<sub>2</sub> receptor</th><th>MC<sub>3</sub> receptor</th><th>MC<sub>4</sub> receptor</th><th>MC<sub>5</sub> receptor</th></tr></thead><tbody><tr><td>Nomenclature</td><td>MC<sub>1</sub> receptor</td><td>MC<sub>2</sub> receptor</td><td>MC<sub>3</sub> receptor</td><td>MC<sub>4</sub> receptor</td><td>MC<sub>5</sub> receptor</td></tr><tr><td>HGNC, UniProt</td><td>MC1R, Q01726</td><td>MC2R, Q01718</td><td>MC3R, P41968</td><td>MC4R, P32245</td><td>MC5R, P33032</td></tr><tr><td>Potency order of endogenous agonists</td><td>α-MSH (POMC, P01189) > β-MSH (POMC, P01189) > ACTH (POMC, P01189), γ-MSH (POMC, P01189)</td><td>ACTH (POMC, P01189)</td><td>γ-MSH (POMC, P01189), β-MSH (POMC, P01189) > ACTH (POMC, P01189), α-MSH (POMC, P01189)</td><td>β-MSH (POMC, P01189) > α-MSH (POMC, P01189), ACTH (POMC, P01189) > γ-MSH (POMC, P01189)</td><td>α-MSH (POMC, P01189) > β-MSH (POMC, P01189) > ACTH (POMC, P01189) > γ-MSH (POMC, P01189)</td></tr><tr><td>Selective agonists</td><td>—</td><td>corticotropin zinc hydroxide</td><td>[D-Trp<sup>8</sup>]γ-MSH [745]</td><td>THIQ [1916]</td><td>—</td></tr><tr><td>Antagonists</td><td>—</td><td>—</td><td>PG-106 (pIC<sub>50</sub> 6.7) [746]</td><td>—</td><td>—</td></tr><tr><td>Selective antagonists</td><td>—</td><td>—</td><td>—</td><td>MBP10 (pIC<sub>50</sub> 10) [132], HS014 (pK<sub>i</sub> 8.5) [1891]</td><td>—</td></tr><tr><td>Labelled ligands</td><td>[125I]NDP-MSH (Agonist) [1138]</td><td>[125I]ACTH-(1-24) (Agonist)</td><td>[125I]NDP-MSH (Agonist) [1138], [125I]SHU9119 (Antagonist) [1581]</td><td>[125I]SHU9119 (Antagonist) (pK<sub>d</sub> 9.2) [1581], [125I]NDP-MSH (Agonist) [1138, 1889]</td><td>[125I]NDP-MSH (Agonist) [1138]</td></tr></tbody></table>

**Comments:** Polymorphisms of the MC₁ receptor have been linked to variations in skin pigmentation. Defects of the MC₂ receptor underlie familial glucocorticoid deficiency. Polymorphisms of the MC₄ receptor have been linked to obesity [328, 586].

## Further reading on Melanocortin receptors

Caruso V et al. (2014) Synaptic changes induced by melanocortin signalling. *Nat. Rev. Neurosci.* **15**: 98-110 [PMID:24588018]

Foord SM et al. (2005) International Union of Pharmacology. XLVI. G protein-coupled receptor list. *Pharmacol Rev* **57**: 279-288 [PMID:15914470]

Renquist BJ et al. (2011) Physiological roles of the melanocortin MC₃ receptor. *Eur. J. Pharmacol.* **660**: 13-20 [PMID:21211527]
# Melatonin receptors

G protein-coupled receptors → Melatonin receptors

**Overview:** Melatonin receptors (nomenclature as agreed by the **NC-IUPHAR Subcommittee on Melatonin Receptors [525]** ) are activated by the endogenous ligands melatonin and clinically used drugs like ramelteon, agomelatine and tasimelteon.

<table><tr><td>Nomenclature</td><td>MT<sub>1</sub> receptor</td><td>MT<sub>2</sub> receptor</td></tr><tr><td>HGNC, UniProt</td><td>MTNR1A, P48039</td><td>MTNR1B, P49286</td></tr><tr><td>Endogenous agonists</td><td>melatonin [78, 524, 526]</td><td>melatonin [78, 524, 526]</td></tr><tr><td>Agonists</td><td>ramelteon [1049], agomelatine [78, 146], tasimelteon [1759]</td><td>agomelatine [78, 146], ramelteon [1049, 1778], tasimelteon [1759]</td></tr><tr><td>Selective agonists</td><td>–</td><td>UCM1014 [2016], IIK7 [587, 2051], 5-methoxy-luzindole (Partial agonist) [526]</td></tr><tr><td>Selective antagonists</td><td>–</td><td>4P-PDOT (pK<sub>i</sub> 8.8–9.4) [78, 526, 527], K185 (pK<sub>i</sub> 9.3) [587, 2051], DH97 (pK<sub>i</sub> 8) [2107]</td></tr><tr><td>Labelled ligands</td><td>[<sup>125</sup>I]SD6 (Agonist) [1245], 2-[<sup>125</sup>I]melatonin (Agonist) [78, 526], [<sup>3</sup>H]melatonin (Agonist) [254]</td><td>[<sup>125</sup>I]SD6 (Agonist) [1245], 2-[<sup>125</sup>I]melatonin (Agonist) [78, 526], [<sup>125</sup>I]DIV880 (Agonist, Partial agonist) [1245], [<sup>3</sup>H]melatonin (Agonist) [254]</td></tr></table>

**Comments:** Melatonin, 2-iodo-melatonin, agomelatine, GR 196429, LY 156735 and ramelteon [1049] are nonselective agonists for MT₁ and MT₂ receptors. (-)-AMMTC displays an ~400-fold greater agonist potency than (+)-AMMTC at rat MT₁ receptors (see AMMTC for structure) [2136]. Luzindole is an MT₁/MT₂ non-selective competitive melatonin receptor antagonist with about 15-25 fold selectivity for the MT₂ receptor [527]. MT₁/MT₂ heterodimers present different pharmacological profiles from MT₁ and MT₂ receptors [84].

The MT₃ binding site of hamster brain and peripheral tissues such as kidney and testis, also termed the ML₂ receptor, binds selectively 2-iodo-[¹²⁵I]5MCA-NAT [1473]. Pharmacological investigations of MT₃ binding sites have primarily been conducted in hamster tissues. At this site, The endogenous ligand N-acetylserotonin [546, 1324, 1473, 1719] and 5MCA-NAT [1719] appear to function as agonists, while prazosin [1324] functions as an antagonist. The MT₃ binding site of hamster kidney was also identified as the hamster homologue of human quinone reductase

2 (NQO2, P16083 [1601, 1602]). The MT₃ binding site activated by 5MCA-NAT in eye ciliary body is positively coupled to adenylate cyclase and regulates chloride secretion [928]. *Xenopus* melanophores and chick brain express a distinct receptor (x420, P49219; c346, P49288, initially termed Mel₁C) coupled to the G₁/o family of G proteins, for which GPR50 has recently been suggested to be a mammalian counterpart [530] although melatonin does not bind to GPR50 receptors. Several variants of the MTNR1B gene have been associated with increased type 2 diabetes risk [1043].

## Further reading on Melatonin receptors

* Cecon E et al. (2018) Melatonin receptors: molecular pharmacology and signalling in the context of system bias. *Br. J. Pharmacol.* **175**: 3263-3280 [PMID:28707298]

* Dubocovich ML et al. (2010) International Union of Basic and Clinical Pharmacology. LXXV. Nomenclature, classification, and pharmacology of G protein-coupled melatonin receptors. *Pharmacol. Rev.* **62**: 343-80 [PMID:20605968]

* Jockers R et al. (2016) Update on melatonin receptors: IUPHAR Review 20. *Br. J. Pharmacol.* **173**: 2702-25 [PMID:27314810]

* Karamitri A et al. (2019) Melatonin in type 2 diabetes mellitus and obesity. *Nat Rev Endocrinol* **15**: 105-125 [PMID:30531911]

* Liu J et al. (2016) MT1 and MT2 Melatonin Receptors: A Therapeutic Perspective. *Annu. Rev. Pharmacol. Toxicol.* **56**: 361-83 [PMID:26514204]

* Zlotos DP et al. (2014) MT1 and MT2 melatonin receptors: ligands, models, oligomers, and therapeutic potential. *J. Med. Chem.* **57**: 3161-85 [PMID:24228714]
# Metabotropic glutamate receptors

G protein-coupled receptors → Metabotropic glutamate receptors

**Overview:** Metabotropic glutamate (mGlu) receptors (nomenclature as agreed by the NC-IUPHAR Subcommittee on Metabotropic Glutamate Receptors [1899]) are a family of G protein-coupled receptors activated by the neurotransmitter glutamate. The mGlu family is composed of eight members (named mGlu1 to mGlu8) which are divided in three groups based on similarities of agonist pharmacology, primary sequence and G protein coupling to effector: Group-I (mGlu1 and mGlu5), Group-II (mGlu2 and mGlu3) and Group-III (mGlu4, mGlu6, mGlu7 and mGlu8) (see Further reading).

Structurally, mGlu are composed of three juxtaposed domains: a core G protein-activating seven-transmembrane domain (TM), common to all GPCRs, is linked via a rigid cysteine-rich domain (CRD) to the Venus Flytrap domain (VFTD), a large bi-lobed extracellular domain where glutamate binds. The structures of the

VFTD of mGlu1, mGlu2, mGlu3, mGlu5 and mGlu7 have been solved [1177, 1482, 1530, 2156]. The structure of the 7 trans-membrane (TM) domains of both mGlu1 and mGlu5 have been solved, and confirm a general helical organization similar to that of other GPCRs, although the helices appear more compacted [383, 515, 2335]. mGlu form constitutive dimers crosslinked by a disulfide bridge. Recent studies revealed the possible formation of heterodimers between either group-I receptors, or within and between group-II and -III receptors [518]. Although well characterized in transfected cells, co-localization and specific pharmacological properties also suggest the existence of such heterodimers in the brain [1493, 2393].

The endogenous ligands of mGlu are L-glutamic acid, L-serine-O-phosphate, N-acetylaspartylglutamate (NAAG) and L-cysteine sulphinic acid. Group-I mGlu receptors may be ac-

tivated by 3,5-DHPG and (S)-3HPG [221] and antagonized by (S)-hexylhomoibotenic acid [1346]. Group-II mGlu receptors may be activated by LY389795 [1483], LY379268 [1483], егумегад [1898 2337], DCG-IV and (2R,3R)-APDC [1899], and antagonised by eGlu [979] and LY307452 [571, 2289]. Group-III mGlu receptors may be activated by L-AP4 and (R,S)-4-PPG [666]. An example of an antagonist selective for mGlu receptors is LY341495, which blocks mGlu2 and mGlu3 at low nanomolar concentrations, mGlu8 at high nanomolar concentrations, and mGlu4, mGlu5, and mGlu7 in the micromolar range [1099]. In addition to orthosteric ligands that directly interact with the glutamate recognition site, allosteric modulators that bind within the TM domain have been described. Negative allosteric modulators are listed separately. The positive allosteric modulators most often act as ‘potentiators’ of an orthosteric agonist response, without significantly activating the receptor in the absence of agonist.

<table><tr><td>Nomenclature</td><td>mGlu<sub>1</sub> receptor</td><td>mGlu<sub>2</sub> receptor</td><td>mGlu<sub>3</sub> receptor</td><td>mGlu<sub>4</sub> receptor</td><td>mGlu<sub>5</sub> receptor</td></tr><tr><td>HGNC, UniProt</td><td>GRM1, Q13255</td><td>GRM2, Q14416</td><td>GRM3, Q14832</td><td>GRM4, Q14833</td><td>GRM5, P41594</td></tr><tr><td>Endogenous agonists</td><td>L-glutamic acid [1705]</td><td>L-glutamic acid [1705]</td><td>L-glutamic acid [1705], NAAG [1906]</td><td>L-glutamic acid [1705]</td><td>L-glutamic acid [1705]</td></tr><tr><td>Agonists</td><td>–</td><td>–</td><td>–</td><td>L-AP4 [2337], L-serine-O-phosphate [2337]</td><td>–</td></tr><tr><td>Selective agonists</td><td>–</td><td>–</td><td>–</td><td>LSP4-2022 [731]</td><td>(S)-(+)-CBPG (Partial agonist) [1373] – Rat, CHPG [1529]</td></tr><tr><td>Antagonists</td><td>LY367385 (pIC<sub>50</sub> 5.1) [400]</td><td>–</td><td>–</td><td>MAP4 (pK<sub>i</sub> 4.6) [792] – Rat</td><td>–</td></tr><tr><td>Selective antagonists</td><td>3-MATIDA (pIC<sub>50</sub> 5.2) [1506] – Rat, (S)-(+)-CBPG (pIC<sub>50</sub> 4.2) [1373] – Rat, (S)-TBPG (pIC<sub>50</sub> 4.2) [417] – Rat, AIDA (pA<sub>2</sub> 4.2) [1507]</td><td>PCCG-4 (pIC<sub>50</sub> 5.1) [1677] – Rat</td><td>–</td><td>–</td><td>ACDPP (pIC<sub>50</sub> 6.9) [202]</td></tr><tr><td>Allosteric modulators</td><td>–</td><td>CBiPES (Positive) (pEC<sub>50</sub> 7) [1010], 4-MPPTS (Positive) (pIC<sub>50</sub> 5.8) [108, 1009, 1010, 1884]</td><td>MNI-137 (Negative) (pIC<sub>50</sub> 7.7) [850] – Rat, VU0650786 (Negative) (pIC<sub>50</sub> 6.4) [560]</td><td>SIB-1893 (Positive) (pEC<sub>50</sub> 6.3–6.8) [1395], MPEP (Positive) (pEC<sub>50</sub> 6.3–6.6) [1395], PHCCC (Positive) (pEC<sub>50</sub> 4.5) [1358]</td><td>alloswitch-1 (Negative) (pIC<sub>50</sub> 8.1) [1714] – Rat, CDPPB (Positive) (pEC<sub>50</sub> 7.6–8) [1100, 1290], MTEP (Negative) (pK<sub>i</sub> 7.8) [246], MPEP (Negative) (pIC<sub>50</sub> 7.4–7.7) [665, 667], fenobam (Negative) (pIC<sub>50</sub> 7.2) [1723]</td></tr><tr><td>Selective allosteric modulators</td><td>BAY 367620 (Negative) (pK<sub>i</sub> 9.5) [309] – Rat, JNJ16259685 (Negative) (pIC<sub>50</sub> 8.9) [1210], Ro01-6128 (Positive) (pK<sub>i</sub> 7.5–7.7) [1118] – Rat, LY456236 (Negative) (pIC<sub>50</sub> 6.9) [1270], CPCCOEt (Negative) (pIC<sub>50</sub> 5.2–5.8) [1293]</td><td>Ro64-5229 (Negative) (pIC<sub>50</sub> 7) [1130] – Rat, biphenylindanone A (Positive) (pEC<sub>50</sub> 7) [203]</td><td>ML337 (Negative) (pIC<sub>50</sub> 6.2) [2286] – Rat</td><td>VU0361737 (Positive) (pEC<sub>50</sub> 6.6) [559], VU0155041 (Positive) (pEC<sub>50</sub> 6.1) [1595]</td><td>VU-1545 (Positive) (pEC<sub>50</sub> 8) [470]</td></tr></table>
<table><tr><td>Nomenclature</td><td>mGlu<sub>6</sub> receptor</td><td>mGlu<sub>7</sub> receptor</td><td>mGlu<sub>8</sub> receptor</td></tr><tr><td>HGNC, UniProt</td><td>GRM6, O15303</td><td>GRM7, Q14831</td><td>GRM8, O00222</td></tr><tr><td>Endogenous agonists</td><td>L-glutamic acid [1705]</td><td>L-glutamic acid [1705]</td><td>L-serine-O-phosphate [1365, 2337], L-glutamic acid [1705]</td></tr><tr><td>Agonists</td><td>–</td><td>LSP4-2022 [731], L-serine-O-phosphate [2337], L-AP4 [2337]</td><td>(S)-3,4-DCPG [2122], L-AP4 [1365]</td></tr><tr><td>Selective agonists</td><td>1-benzyl-APDC [2158] – Rat, homo-AMPA [264]</td><td>–</td><td>–</td></tr><tr><td>Antagonists</td><td>MAP4 (pIC<sub>50</sub> 3.5) [1706] – Rat, THPG [2126]</td><td>–</td><td>MPPG (pIC<sub>50</sub> 4.3) [2337]</td></tr><tr><td>Allosteric modulators</td><td>–</td><td>MMPIP (Negative) (pIC<sub>50</sub> 6.1–7.6) [1594, 2063] – Rat, ADX71743 (Negative) (pIC<sub>50</sub> 7.2) [1031], AMN082 (Positive) (pEC<sub>50</sub> 6.5–6.8) [1463], XAP044 (Negative) (pIC<sub>50</sub> 5.6) [676]</td><td>VU0422288 (Positive) (pK<sub>B</sub> 6.7) [978], VU0155094 (Positive) (pK<sub>B</sub> 5) [978]</td></tr></table>

**Comments:** The activity of NAAG as an agonist at mGlu<sub>3</sub> receptors was questioned on the basis of contamination with glutamate [374, 631], but this has been refuted [1553].

Radioligand binding using a variety of radioligands has been conducted on recombinant receptors (for example, [³H]R214127 [1209] and [³H]YM298198 [1125] at mGlu<sub>1</sub> receptors and [³H]M-MPEP [665] and [³H]methoxymethyl-MTEP [51] at mGlu<sub>5</sub> receptors; [³H]LY341495 and [³H]eglumegad for mGlu<sub>2</sub> and mGlu<sub>3</sub> receptors [1008, 1906]). Although a number of radioligands have been used to examine binding in native tissues, correlation with individual subtypes is limited. Many pharmacological agents have not been fully tested across all known subtypes

of mGlu receptors and may have unappreciated biased or neutral activity at other subtypes [849]. Potential differences linked to the species (e.g. human versus rat or mouse) of the receptors and the receptor splice variants are generally not known. The influence of receptor expression level on pharmacology and selectivity has not been controlled for in most studies, particularly those involving functional assays of receptor coupling.

(S)-(+)-CBPG is an antagonist at mGlu<sub>1</sub>, but is an agonist (albeit of reduced efficacy) at mGlu<sub>5</sub> receptors. DCG-IV also exhibits agonist activity at NMDA glutamate receptors [2183], and is an antagonist at all Group-III mGluRs with an IC<sub>50</sub> of 30µM. A potential novel metabotropic glutamate receptor coupled to phospho-

inositide turnover has been observed in rat brain; it is activated by 4-methylhomoibotenic acid (ineffective as an agonist at recombinant Group I metabotropic glutamate receptors), but is resistant to LY341495 [392]. There are also reports of a distinct metabotropic glutamate receptor coupled to phospholipase D in rat brain, which does not readily fit into the current classification [1112, 1675]

A related class C receptor composed of two distinct subunits, T1R1 + T1R3 is also activated by glutamate and is responsible for umami taste detection.

All selective antagonists at metabotropic glutamate receptors are competitive.

Further reading on Metabotropic glutamate receptors

Conn PJ et al. (1997) Pharmacology and functions of metabotropic glutamate receptors. *Annu. Rev. Pharmacol. Toxicol.* **37**: 205-237 [PMID:9131252]

Ferraguti F et al. (2006) Metabotropic glutamate receptors. *Cell Tissue Res.* **326**: 483-504 [PMID:16847639]

Nicoletti F et al. (2011) Metabotropic glutamate receptors: from the workbench to the bedside. *Neuropharmacology* **60**: 1017-41 [PMID:21036182]

Niswender CM et al. (2010) Metabotropic glutamate receptors: physiology, pharmacology, and disease. *Annu. Rev. Pharmacol. Toxicol.* **50**: 295-322 [PMID:20055706]

Pin JP et al. (2016) Organization and functions of mGlu and GABAB receptor complexes. *Nature* **540**: 60-68 [PMID:27905440]

Rondard P et al. (2011) The complexity of their activation mechanism opens new possibilities for the modulation of mGlu and GABAB class C G protein-coupled receptors. *Neuropharmacology* **60**: 82-92 [PMID:20713070]
# Motilin receptor

G protein-coupled receptors → Motilin receptor

**Overview:** Motilin receptors (provisional nomenclature) are activated by motilin (MLN, P12872), a 22 amino-acid peptide derived from a precursor (MLN, P12872), which may also generate a motilin-associated peptide (MLN, P12872). These receptors promote gastrointestinal motility and are suggested to be responsible for the gastrointestinal prokinetic effects of certain macrolide antibiotics (often called motilides; e.g. erythromycin), although for many of these molecules the evidence is sparse.

<table><tr><td>Nomenclature</td><td>motilin receptor</td></tr><tr><td>HGNC, UniProt</td><td>MLNR, O43193</td></tr><tr><td>Endogenous agonists</td><td>motilin (MLN, P12872) [422, 1400, 1401, 1402]</td></tr><tr><td>Agonists</td><td>alemcinal [2117], erythromycin [588, 2117], azithromycin [241]</td></tr><tr><td>Selective agonists</td><td>camicinal [113, 1863], mitemcinal [1123, 2085] – Rabbit</td></tr><tr><td>Selective antagonists</td><td>MA-2029 (pA<sub>2</sub> 9.2) [2048], GM-109 (pIC<sub>50</sub> 8) [808] – Rabbit</td></tr><tr><td>Labelled ligands</td><td>[<sup>125</sup>I]motilin (human) (Agonist) [588]</td></tr></table>

**Comments:** In terms of structure, the motilin receptor has closest homology with the ghrelin receptor. Thus, the human motilin receptor shares 52% overall amino acid identity with the ghrelin receptor and 86% in the transmembrane regions [834, 2085, 2117]. However, differences between the N-terminus regions of these receptors means that their cognate peptide ligands do not readily activate each other [448, 1863]. In laboratory rodents, the gene encoding the motilin precursor appears to be absent, while the receptor appears to be a pseudogene [834, 1861]. Functions of motilin (MLN, P12872) are not usually detected in rodents, al-

though brain and other responses to motilin and the macrolide alemcinal have been reported and the mechanism of these actions is obscure [1424, 1587]. Notably, in some non-laboratory rodents (e.g. the North American kangaroo rat (Dipodomys) and mouse (Microdipodops) a functional form of motilin may exist but the motilin receptor is non-functional [1269]. Marked differences in ligand affinities for the motilin receptor in dogs and humans may be explained by significant differences in receptor structure [1862]. Note that for the complex macrolide structures, selectivity of action has often not been rigorously examined and other ac-

tions are possible (e.g. P2X inhibition by erythromycin; [2430]). Small molecule motilin receptor agonists are now described [1269, 1863, 2293]. The motilin receptor does not appear to have constitutive activity [897]. Although not proven, the existence of biased agonism at the receptor has been suggested [1402, 1462, 1860]. A truncated 5-transmembrane structure has been identified but this is without activity when transfected into a host cell [588]. Receptor dimerisation has not been reported.

## Further reading on Motilin receptor

* De Smet B et al. (2009) Motilin and ghrelin as prokinetic drug targets. *Pharmacol. Ther.* **123**: 207-23 [PMID:19427331]

* Marrinan SL et al. (2018) A randomized, double-blind, placebo-controlled trial of camicinal in Parkinson's disease. *Mov. Disord.* **33**: 329-332 [PMID:29278279]

* Sanger GJ et al. (2016) Ghrelin and motilin receptors as drug targets for gastrointestinal disorders. *Nat Rev Gastroenterol Hepatol* **13**: 38-48 [PMID:26392067]
# Neuromedin U receptors

G protein-coupled receptors → Neuromedin U receptors

**Overview:** Neuromedin U receptors (provisional nomenclature as recommended by **NC-IUPHAR** [612]) are activated by the endogenous 25 amino acid peptide neuromedin U (neuromedin U-25 (NMU, P48645), NmU-25), a peptide originally isolated from pig spinal cord [1458]. In humans, NmU-25 appears to be the sole product of a precursor gene (NMU, P48645) showing a broad tissue distribution, but which is expressed at highest levels

in the upper gastrointestinal tract, CNS, bone marrow and fetal liver. Much shorter versions of NmU are found in some species, but not in human, and are derived at least in some instances from the proteolytic cleavage of the longer NmU. Despite species differences in NmU structure, the C-terminal region (particularly the C-terminal pentapeptide) is highly conserved and contains biological activity. Neuromedin S (neuromedin S-33 (NMS, Q5H8A3))

has also been identified as an endogenous agonist [1497]. NmS-33 is, as its name suggests, a 33 amino-acid product of a precursor protein derived from a single gene and contains an amidated C-terminal heptapeptide identical to NmU. NmS-33 appears to activate NMU receptors with equivalent potency to NmU-25.

Nomenclature

NMU1 receptor

NMU2 receptor

HGNC, UniProt

NMUR1, Q9HB89

NMUR2, Q9GZQ4

Antagonists

-

R-PSOP (pK<sub>B</sub> 7) [1303]

**Comments:** NMU1 and NMU2 couple predominantly to G<sub>q/11</sub> although there is evidence of good coupling to G<sub>i/o</sub> [235, 910, 918]. NMU1 and NMU2 can be labelled with [<sup>125</sup>I]-NmU and [<sup>125</sup>I]-NmS (of various species, e.g. [1432]), BODIPY® TMR-NMU or Cy3B-NMU-8 [235]. A range of radiolabelled (<sup>125</sup>I-), fluorescently labelled (e.g. Cy3, Cy5, rhodamine and FAM) and biotin labelled versions of neuromedin U-25 (NMU, P48645) and neuromedin S-33 (NMS, Q5H8A3) are now commercially available.

## Further reading on Neuromedin U receptors

*   Brighton PJ et al. (2004) Neuromedin U and its receptors: structure, function, and physiological roles. *Pharmacol. Rev.* **56**: 231-48 [PMID:15169928]

*   Budhiraja S et al. (2009) Neuromedin U: physiology, pharmacology and therapeutic potential. *Fun-dam Clin Pharmacol* **23**: 149-57 [PMID:19645813]

*   Mitchell JD et al. (2009) Emerging pharmacology and physiology of neuromedin U and the struc-turally related peptide neuromedin S. *Br. J. Pharmacol.* **158**: 87-103 [PMID:19519756]

*   Novak CM. (2009) Neuromedin S and U. *Endocrinology* **150**: 2985-7 [PMID:19549882]
# Neuropeptide FF/neuropeptide AF receptors

G protein-coupled receptors → Neuropeptide FF/neuropeptide AF receptors

**Overview:** The Neuropeptide FF receptor family contains two subtypes, NPFF1 and NPFF2 (**provisional nomenclature [612]**), which exhibit high affinities for neuropeptide FF (NPFF,

O15130) and RFamide related peptides (RFRP: precursor gene symbol NPVF, Q9HCQ7). NPFF1 is broadly distributed in the central nervous system with the highest levels found in the limbic system

and the hypothalamus. NPFF2 is present in high density in the superficial layers of the mammalian spinal cord where it is involved in nociception and modulation of opioid functions.

<table><tr><td>Nomenclature</td><td>NPFF1 receptor</td><td>NPFF2 receptor</td></tr><tr><td>HGNC, UniProt</td><td>NPFFR1, Q9GZQ6</td><td>NPFFR2, Q9Y5X5</td></tr><tr><td>Potency order of endogenous ligands</td><td>RFRP-1 (NPVF, Q9HCQ7) > RFRP-3 (NPVF, Q9HCQ7) > FMRFneuropeptide FF (NPFF, O15130) > neuropeptide AF (NPFF, O15130) > neuropeptide SF (NPFF, O15130), QRFP43 (QRFP, P83859), PrRP-31 (PRLH, P81277) [728]</td><td>neuropeptide AF (NPFF, O15130), neuropeptide FF (NPFF, O15130) > PrRP-31 (PRLH, P81277) > FMRF, QRFP43 (QRFP, P83859) > neuropeptide SF (NPFF, O15130) [728]</td></tr><tr><td>Endogenous agonists</td><td>neuropeptide FF (NPFF, O15130) [728, 729, 1476], RFRP-3 (NPVF, Q9HCQ7) [729, 730, 1476]</td><td>neuropeptide FF (NPFF, O15130) [729, 1475]</td></tr><tr><td>Selective agonists</td><td>–</td><td>dNPA [1829], AC263093 [1194]</td></tr><tr><td>Antagonists</td><td>RF9 (pK<sub>i</sub> 7.2) [1974]</td><td>–</td></tr><tr><td>Selective antagonists</td><td>AC262620 (pK<sub>i</sub> 7.7–8.1) [1194], AC262970 (pK<sub>i</sub> 7.4–8.1) [1194]</td><td>–</td></tr><tr><td>Labelled ligands</td><td>[125I]Y-RFRP-3 (Agonist) [729], [3H]NPVF (Agonist) [2095], [125I]NPFF (Agonist) [728]</td><td>[125I]EYF (Agonist) [1476], [3H]EYF (Agonist) [2095], [125I]NPFF (Agonist) [728]</td></tr></table>

**Comments:** An orphan receptor *GPR83* (Q9NYM4) shows sequence similarities with NPFF1, NPFF2, PrRP and QRFP receptors. The antagonist RF9 is selective for NPFF receptors, but does not distinguish between the NPFF1 and NPFF2 subtypes (pK<sub>i</sub> 7.1 and 7.2, respectively, [1974]).

## Further reading on Neuropeptide FF/neuropeptide AF receptors

*Moulédous L et al.* (2010) Opioid-modulating properties of the neuropeptide FF system. *Bio factors* **36**: 423-9 [PMID:20803521]

*Vyas N et al.* (2006) Structure-activity relationships of neuropeptide FF and related peptidic and non-peptidic derivatives. *Peptides* **27**: 990-6 [PMID:16490282]

*Yang HY et al.* (2008) Modulatory role of neuropeptide FF system in nociception and opiate analgesia. *Neuropeptides* **42**: 1-18 [PMID:17854890]
# Neuropeptide S receptor

G protein-coupled receptors → Neuropeptide S receptor

**Overview:** The neuropeptide S receptor (NPS, provisional nomenclature [612]) responds to the 20 amino-acid peptide neuropeptide S derived from a precursor (NPS, P0C0P6).

<table><tr><td>Nomenclature</td><td>NPS receptor</td></tr><tr><td>HGNC, UniProt</td><td>NPSR1, Q6W5P4</td></tr><tr><td>Endogenous agonists</td><td>neuropeptide S (NPS, P0C0P6) [2360]</td></tr><tr><td>Selective agonists</td><td>PWT1-NPS [1840] – Mouse</td></tr><tr><td>Selective antagonists</td><td>NCGC 84 (pA<sub>2</sub> 9) [2127], SHA 68 (pA<sub>2</sub> 8.1) [1841] – Mouse, RTI-118 [2428]</td></tr><tr><td>Labelled ligands</td><td>[<sup>125</sup>I]Tyr<sup>10</sup>NPS (human) (Agonist) [2360]</td></tr></table>

**Comments:** Multiple single-nucleotide polymorphisms (SNP) and several splice variants have been identified in the human NPS receptor. The most interesting of these is an Asn-Ile exchange at position 107 (Asn<sup>107</sup>Ile). The human NPS receptor Asn<sup>107</sup>Ile dis-

played similar binding affinity but higher NPS potency (by approx. 10-fold) than human NPS receptor Asn107 [1787]. Several epidemiological studies reported an association between Asn<sup>107</sup>Ile receptor variant and susceptibility to panic disorders [507, 510,

1629, 1758]. The SNP Asn<sup>107</sup>Ile has also been linked to sleep behavior [727], inflammatory bowel disease [440], schizophrenia [1254], increased impulsivity and ADHD symptoms [1186]. Interestingly, a carboxy-terminal splice variant of human NPS receptor was found to be overexpressed in asthmatic patients [1193].

## Further reading on Neuropeptide S receptor

Grund T et al. (2019) Brain neuropeptide S: via GPCR activation to a powerful neuromodulator of socio-emotional behaviors. *Cell Tissue Res.* **375**: 123-132 [PMID:30112573]

Guerrini R et al. (2010) Neurobiology, pharmacology, and medicinal chemistry of neuropeptide S and its receptor. *Med Res Rev* **30**: 751-77 [PMID:19824051]

Ruzza C et al. (2017) Neuropeptide S receptor ligands: a patent review (2005-2016). *Expert Opin Ther Pat* **27**: 347-362 [PMID:27788040]

Xu YL et al. (2004) Neuropeptide S: a neuropeptide promoting arousal and anxiolytic-like effects. *Neuron* **43**: 487-497 [PMID:15312648]
# Neuropeptide W/neuropeptide B receptors

G protein-coupled receptors → Neuropeptide W/neuropeptide B receptors

**Overview:** The neuropeptide BW receptor 1 (NPBW1, **pro-**
**visional nomenclature [612]**)) is activated by two 23-
amino-acid peptides, neuropeptide W (**neuropeptide W-23**
(NPW, Q8N729)) and neuropeptide B (**neuropeptide B-23** (NPB,
Q8NG41)) [638, 1953]. C-terminally extended forms of the pep-
tides (**neuropeptide W-30** (NPW, Q8N729) and neuropeptide B-29

(NPB, Q8NG41)) also activate NPBW1 [233]. Unique to both forms
of neuropeptide B is the N-terminal bromination of the first tryp-
tophan residue, and it is from this post-translational modification
that the nomenclature NPB is derived. These peptides were first
identified from bovine hypothalamus and therefore are classed
as neuropeptides. Endogenous variants of the peptides with-

out the N-terminal bromination, des-Br-neuropeptide B-23 (NPB,
Q8NG41) and des-Br-neuropeptide B-29 (NPB, Q8NG41), were
not found to be major components of bovine hypothalamic tis-
sue extracts. The NPBW2 receptor is activated by the short and
C-terminal extended forms of neuropeptide W and neuropeptide
B [233].

Nomenclature

NPBW1 receptor

NPBW2 receptor

HGNC, UniProt

NPBWR1, P48145

NPBWR2, P48146

Potency order of endogenous ligands

neuropeptide B-29 (NPB, Q8NG41) > neuropeptide B-23 (NPB,
Q8NG41) > neuropeptide W-23 (NPW, Q8N729) >
neuropeptide W-30 (NPW, Q8N729) [233]

neuropeptide W-23 (NPW, Q8N729) > neuropeptide W-30 (NPW,
Q8N729) > neuropeptide B-29 (NPB, Q8NG41) >
neuropeptide B-23 (NPB, Q8NG41) [233]

Selective agonists

Ava3 [1038], Ava5 [1038]

-

Labelled ligands

[¹²⁵I]NPW-23 (human) (Agonist) [1976]

[¹²⁵I]NPW-23 (human) (Agonist) [1953]

**Comments:** Potency measurements were conducted with heterologously-expressed receptors with a range of 0.14-0.57 nM (NPBW1) and 0.98-21 nM (NPBW2).

NPBW1/- mice show changes in social behavior, suggesting that the NPBW1 pathway may have an important role in the emotional responses of social interaction [1537].

For a review of the contribution of neuropeptide B/W to social
dominance, see Watanabe and Yamamoto, 2015 [2270]. It has
been reported that neuropeptide W may have a key role in the
gating of stressful stimuli when mice are exposed to novel envi-
ronments [1512].

Two antagonists have been discovered and reported to have affin-

ity for NPBW1, ML181 and ML250, the latter exhibiting improved selectivity (100 fold) for NPBW1 compared to MCH1 receptors [762, 763]. Computational insights into the binding of antagonists to this receptor have also been described [1667].

Further reading on Neuropeptide W/neuropeptide B receptors

Sakurai T. (2013) NPBWR1 and NPBWR2: Implications in Energy Homeostasis, Pain, and Emotion. *Front Endocrinol (Lausanne)* **4**: 23 [PMID:23515889]

Singh G et al. (2006) Neuropeptide B and W: neurotransmitters in an emerging G-protein-coupled receptor system. *Br. J. Pharmacol.* **148**: 1033-41 [PMID:16847439]
# Neuropeptide Y receptors

G protein-coupled receptors → Neuropeptide Y receptors

**Overview:** Neuropeptide Y (NPY) receptors (nomenclature as **agreed by the NC-IUPHAR Subcommittee on Neuropeptide Y Receptors** [1444]) are activated by the endogenous peptides neuropeptide Y (NPY, P01303), neuropeptide Y-(3-36), peptide YY (PYY, P10082), PYY-(3-36) and pancreatic polypeptide (PPY, P01298) (PP). The receptor originally identified as the Y3 receptor has been identified as the CXCR4 chemokine receptor

(originally named LESTR, [1310]). The y6 receptor is a functional gene product in mouse, absent in rat, but contains a frameshift mutation in primates producing a truncated non-functional gene [743]. Many of the agonists exhibit differing degrees of selectivity dependent on the species examined. For example, the potency of PP is greater at the rat Y4 receptor than at the human receptor [566]. In addition, many agonists lack selectivity

for individual subtypes, but can exhibit comparable potency against pairs of NPY receptor subtypes, or have not been examined for activity at all subtypes. [$^{125}$I]-PYY or [$^{125}$I]-NPY can be used to label Y1, Y2, Y5 and y6 subtypes non-selectively, while [$^{125}$I][cPP(1-7), NPY(19-23), Ala$^{31}$, Aib$^{32}$, Gln$^{34}$]hPP may be used to label Y5 receptors preferentially (note that cPP denotes chicken peptide sequence and hPP is the human sequence).

<table><thead><tr><th></th><th>Y<sub>1</sub> receptor</th><th>Y<sub>2</sub> receptor</th><th>Y<sub>4</sub> receptor</th><th>Y<sub>5</sub> receptor</th><th>Y<sub>6</sub> receptor</th></tr></thead><tbody><tr><td>Nomenclature</td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>HGNC, UniProt</td><td>NPY1R, P25929</td><td>NPY2R, P49146</td><td>NPY4R, P50391</td><td>NPY5R, Q15761</td><td>NPY6R, Q99463</td></tr><tr><td>Potency order of endogenous ligands</td><td>neuropeptide Y = peptide YY &gt;&gt; pancreatic polypeptide</td><td>peptide YY = peptide YY(3-36) = neuropeptide Y = neuropeptide Y(3-36) &gt;&gt; pancreatic polypeptide</td><td>pancreatic polypeptide &gt;&gt; neuropeptide Y = peptide YY</td><td>neuropeptide Y &gt; peptide YY &gt; pancreatic polypeptide</td><td>neuropeptide Y = peptide YY &gt; pancreatic polypeptide</td></tr><tr><td>Endogenous agonists</td><td>neuropeptide Y (NPY, P01303), peptide YY (PYY, P10082)</td><td>PYY-(3-36) (PYY, P10082) [677, 692], neuropeptide Y (NPY, P01303), neuropeptide Y-(3-36) (NPY, P01303), peptide YY (PYY, P10082)</td><td>pancreatic polypeptide (PPY, P01298) [106, 1327, 2149, 2368]</td><td>—</td><td>—</td></tr><tr><td>Agonists</td><td>[Leu<sup>31</sup>,Pro<sup>34</sup>]NPY [430], [Leu<sup>31</sup>,Pro<sup>34</sup>]PYY (human), [Pro<sup>34</sup>]NPY, [Pro<sup>34</sup>]PYY (human)</td><td>—</td><td>—</td><td>—</td><td>—</td></tr><tr><td>Selective agonists</td><td>—</td><td>—</td><td>—</td><td>[Ala<sup>31</sup>,Aib<sup>32</sup>]NPY (pig) [287]</td><td>—</td></tr><tr><td>Selective antagonists</td><td>BIBO3304 (pIC<sub>50</sub> 9.5) [2303], BIBP3226 (pK<sub>i</sub> 8.1–9.3) [513, 2304]</td><td>BIIE0246 (pIC<sub>50</sub> 8.5) [511], JNJ-5207787 (pIC<sub>50</sub> 6.9–7.1) [198]</td><td>—</td><td>L-152,804 (pK<sub>i</sub> 7.6) [1037]</td><td>—</td></tr><tr><td>Selective allosteric modulators</td><td>—</td><td>—</td><td>niclosamide (Positive) [1988]</td><td>—</td><td>—</td></tr><tr><td>Labelled ligands</td><td>[<sup>3</sup>H]BIBP3226 (Antagonist) (pK<sub>d</sub> 8.7), [<sup>125</sup>I][Leu<sup>31</sup>,Pro<sup>34</sup>]NPY (Agonist)</td><td>[<sup>125</sup>I]PYY-(3-36) (human) (Agonist)</td><td>[<sup>125</sup>I]PP (human) (Agonist)</td><td>[<sup>125</sup>I][cPP(1-7), NPY(19-23), Ala<sup>31</sup>, Aib<sup>32</sup>, Gln<sup>34</sup>]hPP (Agonist) [532] – Rat</td><td>—</td></tr><tr><td>Comments</td><td>Note that Pro<sup>34</sup>-containing NPY and PYY can also bind Y<sub>4</sub> and Y<sub>5</sub> receptors, so strictly speaking are not selective, but are the 'preferred' agonists.</td><td>—</td><td>—</td><td>—</td><td>—</td></tr></tbody></table>
**Comments:** The Y₁ agonists indicated are selective relative to Y₂ receptors. BIBP3226 is selective relative to Y₂, Y₄ and Y₅ receptors [691]. NPY-(13-36) is Y₂ selective relative to Y₁ and Y₅ receptors. PYY-(3-36) is Y₂ selective relative to Y₁ receptors. Note that Pro34-containing NPY and PYY can also bind Y₄ and Y₅, thus they are selective only relative to Y₂. The y₆ receptor is a pseudogene in humans, but is functional in mouse, rabbit and some other mammals.

Further reading on Neuropeptide Y receptors

Bowers ME *et al*. (2012) Neuropeptide regulation of fear and anxiety: Implications of cholecystokinin, endogenous opioids, and neuropeptide Y. *Physiol. Behav.* **107**: 699-710 [PMID:22429904]

Michel MC *et al*. (1998) XVI. International Union of Pharmacology recommendations for the nomenclature of neuropeptide Y, peptide YY and pancreatic polypeptide receptors. *Pharmacol. Rev.* **50**: 143-150 [PMID:9549761]

Pedragosa-Badia X *et al*. (2013) Neuropeptide Y receptors: how to get subtype selectivity. *Front Enzyme (Lausanne)* **4**: 5 [PMID:23382728]

Zhang L *et al*. (2011) The neuropeptide Y system: pathophysiological and therapeutic implications in obesity and cancer. *Pharmacol. Ther.* **131**: 91-113 [PMID:21439311]

Neurotensin receptors

G protein-coupled receptors → Neurotensin receptors

**Overview:** Neurotensin receptors (nomenclature as recommended by **NC-IUPHAR [612]**) are activated by the endogenous tridecapeptide neurotensin (pGlu-Leu-Tyr-Glu-Asn-Lys-Pro-Arg-Arg-Pro-Tyr-Ile-Leu) derived from a precursor (NTS, 30990), which also generates neuromedin N, an agonist at the NTS₂ receptor. [³H]neurotensin (human, mouse, rat) and [¹²⁵I]neurotensin (human, mouse, rat) may be used to label NTS₁ and NTS₂ receptors at 0.1-0.3 and 3-5 nM concentrations respectively.

<table><tr><td>Nomenclature</td><td>NTS<sub>1</sub> receptor</td><td>NTS<sub>2</sub> receptor</td></tr><tr><td>HGNC, UniProt</td><td>NTSR1, P30989</td><td>NTSR2, O95665</td></tr><tr><td>Potency order of endogenous ligands</td><td>neurotensin (NTS, P30990) > neuromedin N (Mouse, Rat) [855]</td><td>neurotensin (NTS, P30990) = neuromedin N (Mouse, Rat) [1411]</td></tr><tr><td>Selective agonists</td><td>JMV449 [1983] – Rat</td><td>levocabastine [1411, 1801]</td></tr><tr><td>Selective antagonists</td><td>meclinitertant (pIC<sub>50</sub> 7.5–8.2) [767]</td><td>–</td></tr><tr><td>Labelled ligands</td><td>[³H]meclinitertant (Antagonist) (pK<sub>d</sub> 8.5) [1188] – Rat</td><td>–</td></tr></table>

**Comments:** Neurotensin (NTS, P30990) appears to be a low-efficacy agonist at the NTS₂ receptor [2222], while the NTS₁ receptor antagonist meclinitertant is an agonist at NTS₂ receptors [2222]. An additional protein, provisionally termed NTS₃ (also known as

NTR3, gp95 and sortilin; ENSG00000134243), has been suggested to bind lipoprotein lipase and mediate its degradation [1585]. It has been reported to interact with the NTS₁ receptor [1388] and the NTS₂ receptor [283], and has been implicated in hormone traf-

ficking and/or neurotensin uptake. A splice variant of the NTS₂ receptor bearing 5 transmembrane domains has been identified in mouse [211] and later in rat [1689].

Further reading on Neurotensin receptors

Boules M *et al*. (2013) Diverse roles of neurotensin agonists in the central nervous system. *Front Endocrinol (Lausanne)* **4**: 36 [PMID:23526754]

Mazella J *et al*. (2012) Neurotensin and its receptors in the control of glucose homeostasis. *Front Endocrinol (Lausanne)* **3**: 143 [PMID:23230428]

Myers RM *et al*. (2009) Cancer, chemistry, and the cell: molecules that interact with the neurotensin receptors. *ACS Chem. Biol.* **4**: 503-25 [PMID:19462983]

Ouyang Q *et al*. (2017) Oncogenic role of neurotensin and neurotensin receptors in various cancers. *Clin. Exp. Pharmacol. Physiol.* **44**: 841-846 [PMID:28556374]
# Opioid receptors

G protein-coupled receptors → Opioid receptors

**Overview:** Opioid and opioid-like receptors are activated by a variety of endogenous peptides including [Met]enkephalin (PENK, P01210) (met), [Leu]enkephalin (PENK, P01210) (leu), β-endorphin (POMC, P01189) (β-end), α-neodynorphin (PDYN, P01213), dynorphin A (PDYN, P01213) (dynA), dynorphin B (PDYN, P01213) (dynB), big dynorphin (PDYN, P01213) (Big dyn), nociceptin/orphanin FQ (PNOC, Q13519) (N/OFQ);

endomorphin-1 and endomorphin-2 are also potential endogenous peptides. The Greek letter nomenclature for the opioid receptors, μ, δ and κ, is well established, and **NC-IUPHAR** considers this nomenclature appropriate, along with the symbols spelled out (mu, delta, and kappa), and the acronyms, MOP, DOP, and KOP. [428, 488, 612]. The human N/OFQ receptor, NOP, is considered 'opioid-related' rather than opioid because,

while it exhibits a high degree of structural homology with the conventional opioid receptors [1478], it displays a distinct pharmacology. Currently there are numerous clinically used drugs, such as morphine and many other opioid analgesics, as well as antagonists such as naloxone, however only for the μ receptor.

<table><tr><td>Nomenclature</td><td>δ receptor</td><td>κ receptor</td></tr><tr><td>HGNC, UniProt</td><td>OPRD1, P41143</td><td>OPRK1, P41145</td></tr><tr><td>Principal endogenous agonists</td><td>β-endorphin (POMC, P01189), [Leu]enkephalin (PENK, P01210), [Met]enkephalin (PENK, P01210)</td><td>big dynorphin (PDYN, P01213), dynorphin A (PDYN, P01213)</td></tr><tr><td>Agonists</td><td>DADLE [2142], etorphine [2142], ethylketocyclazocine [2142]</td><td>–</td></tr><tr><td>Sub/family-selective agonists</td><td>BU08028 (Partial agonist) [1076]</td><td>BU08028 [1076]</td></tr><tr><td>Selective agonists</td><td>UFP-512 [2215], BW373U86 [1220], ADL5859 [1220], DPDPE [1511, 2142], [D-Ala<sup>2</sup>]deltorphin II [568], ADL5747 [1221], SNC80 [292, 1757]</td><td>U50488 [345, 1671, 1973, 2142, 2230, 2437, 2439], enadoline [934, 1571], U69593 [1192, 2142], salvinorin A [281, 1825]</td></tr><tr><td>Antagonists</td><td>UFP-505 (pK<sub>i</sub> 9.8) [494, 495], naltrexone (pK<sub>i</sub> 8) [2142], naloxone (pK<sub>i</sub> 7.2) [2142]</td><td>buprenorphine (pK<sub>i</sub> 9.1–10.2) [2142, 2439], nalmefene (pK<sub>i</sub> 9.5) [2142], naltrexone (pK<sub>i</sub> 8.4–9.4) [1671, 1973, 2142], naloxone (pK<sub>i</sub> 7.6–8.6) [1671, 1973, 2142, 2437, 2439]</td></tr><tr><td>Sub/family-selective antagonists</td><td>AT-076 (pK<sub>i</sub> 7.7) [2142, 2412]</td><td>AT-076 (pK<sub>i</sub> 8.9) [2142, 2413]</td></tr><tr><td>Selective antagonists</td><td>naltriben (pK<sub>i</sub> 10) [2003, 2142], naltrindole (pK<sub>i</sub> 9.7) [1725, 2142], TIPP<sub>ψ</sub> (Inverse agonist) (pK<sub>i</sub> 9) [1888, 2142]</td><td>nor-binaltorphimine (pK<sub>i</sub> 8.9–11) [1671, 1724, 1973, 2142, 2437, 2439], 5'-guanidinonaltrindole (pK<sub>i</sub> 9.7–9.9) [1017, 1671, 2031], JDTic (pK<sub>i</sub> 9–9.4) [1520, 2121, 2413]</td></tr><tr><td>Labelled ligands</td><td>[<sup>3</sup>H]naltrindole (Antagonist) (pK<sub>d</sub> 10.4) [2364] – Rat, [<sup>3</sup>H][D-Ala<sup>2</sup>]deltorphin I (Selective Agonist) [2027], [<sup>3</sup>H]diprenorphine (Agonist) [56, 2142], [<sup>3</sup>H]DPDPE (Agonist) [28], [<sup>3</sup>H]deltorphin II (Agonist) [284], [<sup>3</sup>H]naltriben (Antagonist) [1264]</td><td>[<sup>3</sup>H]diprenorphine (Antagonist) (pK<sub>d</sub> 9.1) [56, 1973], [<sup>3</sup>H]U69593 (Agonist) [1192, 1671, 1973], [<sup>3</sup>H]enadoline (Agonist) [1975]</td></tr></table>
<table><tr><td>Nomenclature</td><td>μ receptor</td><td>NOP receptor</td></tr><tr><td>HGNC, UniProt</td><td>OPRM1, P35372</td><td>OPRL1, P41146</td></tr><tr><td>Potential endogenous agonists</td><td>endomorphin-1, endomorphin-2</td><td>–</td></tr><tr><td>Principal endogenous agonists</td><td>β-endorphin (POMC, P01189), [Met]enkephalin (PENK, P01210), [Leu]enkephalin (PENK, P01210)</td><td>–</td></tr><tr><td>Endogenous agonists</td><td>–</td><td>nociceptin/orphanin FQ (PNOC, Q13519) [11, 165, 1630]</td></tr><tr><td>Agonists</td><td>levorphanol [797], hydromorphone [2287], fentanyl [2142], buprenorphine (Partial agonist) [2142], methadone [1727], UFP-505 [494, 495], codeine [2142], tapentadol [2163], pethidine [1727]</td><td>–</td></tr><tr><td>Sub/family-selective agonists</td><td>BU08028 (Partial agonist) [1076]</td><td>cebranopadol [1292], BU08028 (Partial agonist) [1076]</td></tr><tr><td>Selective agonists</td><td>sufentanil [2224], DAMGO [796, 2142], loperamide [356], morphine [717, 2142], PL017 [336, 2142]</td><td>N/OFQ-(1-13)-NH<sub>2</sub> [165, 764, 1418, 1630], Ac-RYYRWK-NH<sub>2</sub> (Partial agonist) [514, 1418], SCH221510 [2208], Ro64-6198 [987, 2301], AT-403 [63]</td></tr><tr><td>Antagonists</td><td>naltrexone (pK<sub>i</sub> 9.1–9.7) [1061, 2142], nalmefene (pK<sub>i</sub> 9.5) [2142], nalorphine (pK<sub>i</sub> 8.9) [2142], naloxone (pK<sub>i</sub> 8.9) [2142], methylnaltrexone (pK<sub>i</sub> 8.7) [2287]</td><td>–</td></tr><tr><td>Sub/family-selective antagonists</td><td>AT-076 (pK<sub>i</sub> 8.8) [2142, 2413]</td><td>AT-076 (pK<sub>i</sub> 8.8) [2413]</td></tr><tr><td>Selective antagonists</td><td>alvimopan (pK<sub>i</sub> 9.3) [1219], levallorphan (pK<sub>i</sub> 8.8–9.3) [1361], CTAP (pK<sub>i</sub> 8.6) [336, 2142]</td><td>UFP-101 (pK<sub>i</sub> 10.2) [294], LY2940094 (pK<sub>i</sub> 10) [2141], compound 24 (pK<sub>i</sub> 9.6) [605], SB 612111 (pK<sub>i</sub> 9.2–9.5) [2017, 2411], J-113397 (pIC<sub>50</sub> 8.3) [1057]</td></tr><tr><td>Allosteric modulators</td><td>BMS-986123 (Neutral) (pK<sub>B</sub> 6) [267], BMS-986121 (Positive) (pK<sub>B</sub> 5.7) [267], BMS-986124 (Neutral) (pK<sub>B</sub> 5.7) [267], BMS-986122 (Positive) (pK<sub>B</sub> 5.3) [267]</td><td>–</td></tr><tr><td>Labelled ligands</td><td>[<sup>3</sup>H]diprenorphine (Antagonist) (pK<sub>d</sub> 10.1) [1780] – Mouse, [<sup>3</sup>H]DAMGO (Agonist) [1780] – Rat, [<sup>3</sup>H]PL017 (Agonist) [825] – Rat</td><td>[<sup>3</sup>H]N/OFQ (Agonist) [514, 1477]</td></tr></table>

**Comments:** Three naloxone-sensitive opioid receptor genes have been identified in humans, and while the μ-receptor in particular may be subject to extensive alternative splicing [1660], these putative isoforms have not been correlated with any of the subtypes of receptor proposed in years past. Opioid receptors may heterodimerize with each other or with other 7TM receptors [1019], and give rise to complexes with a unique pharmacology, however, evidence for such heterodimers in native cells is equivocal and the consequences of this heterodimerization for signalling remains largely unknown. For μ-opioid receptors at least, dimerization does not seem to be required for signalling [1180]. A distinct met-enkephalin receptor lacking structural resemblance to the opioid receptors listed has been identified (OGFR, 9NZT2) and

termed an opioid growth factor receptor [2409].

endomorphin-1 and endomorphin-2 have been identified as highly selective, putative endogenous agonists for the μ-opioid receptor. At present, however, the mechanisms for endomorphin synthesis *in vivo* have not been established, and there is no gene identified that encodes for either. Thus, the status of these peptides as endogenous ligands remains unproven.

Two areas of increasing importance in defining opioid receptor function are the presence of functionally relevant single nucleotide polymorphisms in human μ-receptors [1613] and the identification of biased signalling by opioid receptor ligands, in particular, compounds previously characterized as antagonists

[255]. Pathway bias for agonists makes general rank orders of potency and efficacy somewhat obsolete, so these do not appear in the table. As ever, the mechanisms underlying the acute and long term regulation of opioid receptor function are the subject of intense investigation and debate.

The richness of opioid receptor pharmacology has been enhanced with the recent discovery of allosteric modulators of μ and δ receptors, notably the positive allosteric modulators and silent allosteric "antagonists" outlined in [267, 268]. Negative allosteric modulation of opioid receptors has been previously suggested [1048], whether all compounds are acting at a similar site remains to be established.
Further reading on Opioid receptors

Butelman ER et al. (2012) κ-opioid receptor/dynorphin system: genetic and pharmacotherapeutic implications for addiction. *Trends Neurosci.* **35**: 587-96 [PMID:22709632]

Cox BM et al. (2015) Challenges for opioid receptor nomenclature: IUPHAR Review 9. *Br. J. Pharmacol.* **172**: 317-23 [PMID:24528283]

Pradhan AA et al. (2011) The delta opioid receptor: an evolving target for the treatment of brain disorders. *Trends Pharmacol. Sci.* **32**: 581-90 [PMID:21925742]

Williams JT et al. (2013) Regulation of μ-opioid receptors: desensitization, phosphorylation, internalization, and tolerance. *Pharmacol. Rev.* **65**: 223-54 [PMID:23321159]

Orexin receptors

G protein-coupled receptors → Orexin receptors

**Overview:** Orexin receptors (nomenclature as agreed by the **NC-IUPHAR** Subcommittee on Orexin receptors [612]) are activated by the endogenous polypeptides orexin-A (*HCRT*, O43612) and orexin-B (*HCRT*, O43612) (also known as

hypocretin-1 and -2; 33 and 28 aa) derived from a common precursor, preproorexin or orexin precursor, by proteolytic cleavage and some typical peptide modifications [1852]. Currently the only orexin receptor ligand in clinical use is *suvorexant*, which is used

as a hypnotic. Orexin receptor crystal structures have been solved [2390, 2392].

<table><tr><td>Nomenclature</td><td>OX<sub>1</sub> receptor</td></tr><tr><td>HGNC, UniProt</td><td>HCRTR1, O43613</td></tr><tr><td>Potency order of endogenous ligands</td><td>orexin-A (HCRT, O43612) &gt; orexin-B (HCRT, O43612)</td></tr><tr><td>Selective agonists</td><td>–</td></tr><tr><td>Antagonists</td><td>SB-649868 (pK<sub>i</sub> 9.3–9.6) [293, 429], *suvorexant* (pK<sub>i</sub> 8.7–9.3) [293, 429, 1513], *filorexant* (pK<sub>i</sub> 8.4–9.1) [293, 429, 2319], *TCS* 1102 (pK<sub>i</sub> 8.5) [148], *almorexant* (pK<sub>i</sub> 7.8–8.5) [293, 581, 1363, 1364, 1367], *Cp-1* (pK<sub>i</sub> 7.6–8) [1363, 1364]</td></tr><tr><td>Selective antagonists</td><td>SB-674042 (70–300-fold selective) (pK<sub>i</sub> 8.7–9.3) [1200, 1363, 1364, 1367], SB-334867 (50–150-fold selective) (pK<sub>i</sub> 7.2–7.9) [1200, 1363, 1364, 1722, 1746, 1991], SB-408124 (60–80-fold selective) (pK<sub>i</sub> 7.2–7.9) [1200, 1364, 1513]</td></tr><tr><td>Labelled ligands</td><td>[<sup>3</sup>H]SB-674042 (Antagonist) (pK<sub>d</sub> 8.3–9.1) [1200, 1364, 1367], [<sup>3</sup>H]-almorexant (Antagonist) (pK<sub>d</sub> 8.6–8.9) [1364, 1367], [<sup>125</sup>I]-orexin-A (Agonist) [1168, 1747, 1852]</td></tr></table>

<table><tr><td>OX<sub>2</sub> receptor</td></tr><tr><td>HCRTR2, O43614</td></tr><tr><td>orexin-A (HCRT, O43612) = orexin-B (HCRT, O43612)</td></tr><tr><td>[Ala<sup>11</sup>, D-Leu<sup>15</sup>]orexin-B [73, 1748], Nag 26 [1535, 1807], YNT-185 [951, 1535]</td></tr><tr><td>SB-649868 (pK<sub>i</sub> 8.9–9.8) [293, 429], *TCS* 1102 (pK<sub>i</sub> 9.7) [148], *suvorexant* (pK<sub>i</sub> 8.9–9.5) [293, 429, 1513], *Cp-1* (pK<sub>i</sub> 8.5–9.3) [1363, 1364], *filorexant* (pK<sub>i</sub> 8.9–9.1) [293, 429, 2319]</td></tr><tr><td>EMPA (300–3000-fold selective) (pK<sub>i</sub> 8.4–9.2) [1363, 1364, 1367, 1513, 2152], JN-10397049 (200–800-fold selective) (pK<sub>i</sub> 7.7–8.4) [429, 1414, 2152], *TCS-OX2-29* (pK<sub>i</sub> 6.9–7.5) [148, 879]</td></tr><tr><td>[<sup>3</sup>H]-almorexant (Selective Antagonist) (pK<sub>d</sub> 8.9–9.8) [1364, 1367], [<sup>3</sup>H]Cp-1 (Selective Antagonist) (pK<sub>d</sub> 9.2–9.4) [1364], [<sup>3</sup>H]EMPA (Selective Antagonist) (pK<sub>d</sub> 8.6–9) [1363, 1367], [<sup>125</sup>I]-orexin-A (Agonist) [1168, 1747, 1852]</td></tr></table>

**Comments:** The primary coupling of orexin receptors to G<sub>q/11</sub> proteins is rather speculative and based on the strong activation of phospholipase C, though recent studies in recombinant cells also stress the importance of G<sub>q/11</sub> [1167]. Coupling of both receptors to G<sub>i/o</sub> and G<sub>s</sub> has also been reported [1046, 1170, 1255, 1769]. For most native cellular responses observed, the G protein pathway is unknown. The relative potency order of endogenous ligands depends on the cellular signal transduction machinery

[1166]. Similarly, [Ala<sup>11</sup>, D-Leu<sup>15</sup>]orexin-B, Nag 26 and YNT-185 may show variable selectivity for OX<sub>2</sub> receptors and are also likely to activate OX<sub>1</sub> receptors [1748, 1807]. Many antagonists and radioligands are not well-characterized, and thus the affinities are uncertain. Among radioligands, [<sup>3</sup>H]SB-674042, [<sup>3</sup>H]EMPA and [<sup>3</sup>H]-almorexant are commercially available. [<sup>3</sup>H]-*TCS* 1102 (pK<sub>d</sub>/OX<sub>1</sub> 8.2, pK<sub>d</sub>/OX<sub>2</sub> 9.0) [293] and Rhodamine Green-orexin-A [445] are also useful radioligand tools. Orexin receptors have

been reported to be able to form complexes with each other and some other GPCRs as well as σ<sub>1</sub> receptors, which might affect the signaling and pharmacology [1169, 1549]. Loss-of-function mutations in the gene encoding the OX<sub>2</sub> receptor underlie canine hereditary narcolepsy [1287]. Antagonists of the orexin receptors are the focus of major drug discovery efforts for their potential to treat insomnia and other disorders of wakefulness [1816], while agonists would likely be useful in human narcolepsy.
Further reading on Orexin receptors

Baimel C et al. (2015) Orexin/hypocretin role in reward: implications for opioid and other addictions. *Br. J. Pharmacol.* **172**: 334-48 [PMID:24641197]

Burdakov D. (2018) Reactive and predictive homeostasis: Roles of orexin/hypocretin neurons. *Neuropharmacology* [PMID:30347195]

Kukkonen JP. (2013) Physiology of the orexinergic/hypocretinergic system: a revisit in 2012. *Am. J. Physiol., Cell Physiol.* **304**: C2-32 [PMID:23034387]

Li SB et al. (2016) Hypocretins, Neural Systems, Physiology, and Psychiatric Disorders. *Curr Psychiatry Rep* **18**: 7 [PMID:26733323]

Mahler SV et al. (2014) Motivational activation: a unifying hypothesis of orexin/hypocretin function. *Nat. Neurosci.* **17**: 1298-303 [PMID:25254979]

Oxoglutarate receptor

G protein-coupled receptors → Oxoglutarate receptor

Overview: Nomenclature as recommended by NC-IUPHAR [455].

Nomenclature oxoglutarate receptor

HGNC, UniProt OXGR1, Q96P68

Endogenous agonists α-ketoglutaric acid [838, 2015]

Further reading on Oxoglutarate receptor

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]

Grimm PR and Welling PA (2017) alpha-Ketoglutarate drives electroneutral NaCl reabsorption in intercalated cells by activating a G-protein coupled receptor. *Oxgr1. Curr. Opin. Nephrol. Hypertens.* **26**: 426-433 [PMID:28771454]
# P2Y receptors

G protein-coupled receptors → P2Y receptors

**Overview:** P2Y receptors (nomenclature as agreed by the NC-IUPHAR Subcommittee on P2Y Receptors [1, 2]) are activated by the endogenous ligands ATP, ADP, uridine triphosphate, uridine diphosphate and UDP-glucose. The relationship of many of the cloned receptors to endogenously ex-

pressed receptors is not yet established and so it might be appropriate to use wording such as 'uridine triphosphate-preferring (or ATP-, etc.) P2Y receptor' or 'P2Y₁-like', etc., until further, as yet undefined, corroborative criteria can be applied [271, 567, 966, 2227, 2281].

Clinically used drugs acting on these receptors include the dinucleoside polyphosphate diquafosol, agonist of the P2Y₂ receptor subtype, approved in Japan for the management of dry eye disease [1207], and the P2Y₁₂ receptor antagonists prasugrel, ticagrelor and cangrelor, all approved as antiplatelet drugs [298, 1734].

<table><thead><tr><th></th><th></th><th></th><th></th><th></th><th></th></tr></thead><tbody><tr><td>Nomenclature</td><td>P2Y₁ receptor</td><td>P2Y₂ receptor</td><td>P2Y₄ receptor</td><td>P2Y₆ receptor</td><td></td></tr><tr><td>HGNC, UniProt</td><td>P2RY1, P47900</td><td>P2RY2, P41231</td><td>P2RY4, P51582</td><td>P2RY6, Q15077</td><td></td></tr><tr><td>Potency order of endogenous ligands</td><td>ADP>ATP</td><td>uridine triphosphate > ATP [1217]</td><td>uridine triphosphate> ATP (at rat recombinant receptors, UTP = ATP)</td><td>uridine diphosphate &gt;&gt; uridine triphosphate > ADP</td><td></td></tr><tr><td>Endogenous agonists</td><td>–</td><td>uridine triphosphate [1087, 1217]</td><td>–</td><td>–</td><td></td></tr><tr><td>Agonists</td><td>ADPβS [2088], 2MeSADP [1882, 2238]</td><td>–</td><td>–</td><td>–</td><td></td></tr><tr><td>Sub/family-selective agonists</td><td>–</td><td>diquafosol [1680], denufosol [1218, 1680, 2388], UTPγS [1217]</td><td>diquafosol [259], denufosol [2388], UTPγS [1218]</td><td>–</td><td></td></tr><tr><td>Selective agonists</td><td>MRS2365 [364], 2-Cl-ADP(α-BH₃) [85]</td><td>MRS2698 [960], 2-thioUTP [549], PSB1114 (EC₅₀ value determined using an IP₃ functional assay) [549, 550, 959]</td><td>MRS4062 [1390], MRS2927 [1390], (N)methanocarba-UTP [1087]</td><td>Rp-5-OMe-UDPαB [706, 774], MRS2957 [1389], MRS2693 [158]</td><td></td></tr><tr><td>Antagonists</td><td>suramin (pKᵢ 5.3) [2238], PPADS (pKᵢ 5.2) [2238]</td><td>–</td><td>–</td><td>–</td><td></td></tr><tr><td>Sub/family-selective antagonists</td><td>–</td><td>reactive blue-2 (pIc₅₀ 6) [981], suramin (pIc₅₀ 4.3) [981, 1882]</td><td>PPADS (pEC₅₀ 2–5) [969], reactive blue-2 (pIc₅₀ 4.7) [185] – Rat</td><td>reactive blue-2 (pKₐ 6) [2228], PPADS (pKₐ 4) [2228], suramin (pKₐ 4) [2228]</td><td></td></tr><tr><td>Selective antagonists</td><td>MRS2500 (pKᵢ 8.8–9.1) [316, 1086], MRS2279 (pKᵢ 7.9) [2238], MRS2179 (pKᵢ 7–7.1) [220, 2238]</td><td>AR-C118925XX (pIc₅₀ ~6) [1064], AR-C126313 (pEC₅₀ 6) [960], PSB-416 (pIc₅₀ 4.7) [873]</td><td>ATP (pKₐ 6.2) [1067]</td><td>MRS2578 (pIc₅₀ 7.4) [1369], MRS2567 (pIc₅₀ 6.9) [1369]</td><td></td></tr><tr><td>Selective allosteric modulators</td><td>BMS compound 16 (Negative) (pKᵢ 6.9) [2417], 2,2'-pyridylisatogen tosylate (Negative) (pIc₅₀ 6.8) [657]</td><td>–</td><td>–</td><td>–</td><td></td></tr><tr><td>Labelled ligands</td><td>[³H]MRS2279 (Antagonist) (pKₐ 8.1) [2238], [³H]2MeSADP (Agonist) [2088], [³⁵S]ADPβS (Agonist)</td><td>–</td><td>–</td><td>MRS4162 (Selective Antagonist) (pEC₅₀ 7.6) [986]</td><td></td></tr></tbody></table>
<table><tr><td>Nomenclature</td><td>P2Y<sub>11</sub> receptor</td><td>P2Y<sub>12</sub> receptor</td><td>P2Y<sub>13</sub> receptor</td><td>P2Y<sub>14</sub> receptor</td></tr><tr><td>HGNC, UniProt</td><td>P2RY11, Q96G91</td><td>P2RY12, Q9H244</td><td>P2RY13, Q9BPV8</td><td>P2RY14, Q15391</td></tr><tr><td>Potency order of endogenous ligands</td><td>ATP>ADP</td><td>ADP>ATP</td><td>ADP>ATP</td><td>uridine diphosphate= UDP-glucose [311]</td></tr><tr><td>Endogenous agonists</td><td>–</td><td>ADP [854]</td><td>–</td><td>–</td></tr><tr><td>Sub/family-selective agonists</td><td>–</td><td>2MeSADP [854], ADPβS [2088]</td><td>2MeSADP [1386], 2MeSATP [1386], ADPβS [1386]</td><td>–</td></tr><tr><td>Selective agonists</td><td>AR-C67085 [102, 408], NF546 [1430], ATPγS [408]</td><td>–</td><td>–</td><td>α,β-methylene-2-thio-UDP [446], MRS2905 [967], 2-thio-UDP [446]</td></tr><tr><td>Antagonists</td><td>–</td><td>cangrelor (pIC<sub>50</sub> 9.4) [970], Ap4A (pIC<sub>50</sub> 6) [1386], 2MeSAMP (pIC<sub>50</sub> 5.4) [2088]</td><td>cangrelor (pIC<sub>50</sub> 8.3) [1386], Ap4A (pIC<sub>50</sub> 6.7) [1386], 2MeSAMP (pIC<sub>50</sub> 5.6) [1386]</td><td>–</td></tr><tr><td>Sub/family-selective antagonists</td><td>suramin (pIC<sub>50</sub> 4.8–6) [408], reactive blue-2 (pIC<sub>50</sub> 5) [408]</td><td>–</td><td>–</td><td>–</td></tr><tr><td>Selective antagonists</td><td>NF157 (pK<sub>i</sub> 7.3) [2170], NF340 (pIC<sub>50</sub> 6.4–7.1) [1430]</td><td>AZD1283 (pK<sub>i</sub> 8) [88, 2419], ARL66096 (pIC<sub>50</sub> 7.9) [932, 933], ticagrelor (pK<sub>i</sub> 7.8) [2414]</td><td>MRS2603 (pIC<sub>50</sub> 6.2) [1094], MRS2211 (pIC<sub>50</sub> 6) [1094]</td><td>PPTN (pK<sub>i</sub> 10.1) [110]</td></tr><tr><td>Labelled ligands</td><td>–</td><td>[<sup>3</sup>H]2MeSADP (Agonist) [2088], [<sup>3</sup>H]PSB-0413 (Antagonist) (pK<sub>d</sub> 8.3–8.5) [548, 1620]</td><td>[<sup>33</sup>P]2MeSADP (Agonist) [1386]</td><td>MRS4174 (Selective Antagonist) (pK<sub>i</sub> 10.1) [1105], MRS4183 (Selective Agonist) [1104]</td></tr></table>

**Comments:** A series of 4-alkyloxyimino derivatives of uridine-5'-triphosphate which could be useful for derivatization as fluorescent P2Y<sub>2/4/6</sub> receptor probes has been recently synthesized [986].

Single nucleotide polymorphisms of the P2Y<sub>1</sub> gene have been associated to different platelet reactivity to ADP ADP [863]. Three frequent nonsynonymous P2Y<sub>2</sub> receptor polymorphisms have been identified, one of which was significantly more common in cystic fibrosis patients. This polymorphism is linked to increases in Ca<sup>2+</sup> influx in transfected cells, and might therefore play a role in disease development [286]. Although uridine triphosphate

(UTP) was also shown to be a biased agonist at P2Y<sub>11</sub>, this is still under debate [1508, 2297]. A group of single nucleotide polymorphisms in the P2Y<sub>12</sub> gene, forming the so called P2Y<sub>12</sub> H2 haplotype, has been associated with increased platelet responsiveness to ADP, increased risk of peripheral arterial disease and with coronary artery disease [321]. The platelet-type bleeding disorder due to P2Y<sub>12</sub> receptor defects is an autosomal recessive condition characterized by mild to moderate mucocutaneous bleeding and excessive bleeding after surgery or trauma. The defect is due to the inability of ADP to induce platelet aggregation [317]. The P2Y<sub>13</sub>

receptor Met-158-Thr polymorphism, which is in linkage disequilibrium with the P2Y<sub>12</sub> locus, is not associated with acute myocardial infarction, diabetes mellitus or related risk factors [47]. The P2Y<sub>14</sub> receptor was previously considered to exclusively bind sugar nucleotides such as UDP-glucose and UDP-galactose [331]. However, more recent evidence with several cell lines has demonstrated that uridine diphosphate (UDP) is 5-fold more potent than UDP-glucose [311]. UDP was also shown to competitively antagonize the UDP-glucose response at the human recombinant P2Y<sub>14</sub> receptor [632].

## Further reading on P2Y receptors

* Abbracchio MP et al. (2006) International Union of Pharmacology LVIII: update on the P2Y G protein-coupled nucleotide receptors: from molecular mechanisms and pathophysiology to therapy. *Pharmacol. Rev.* **58**: 281-341 [PMID:16968944]

* Jacobson KA et al. (2015) Nucleotides Acting at P2Y Receptors: Connecting Structure and Function. *Mol. Pharmacol.* **88**: 220-30 [PMID:25837834]

von Kügelgen I et al. (2016) Pharmacology and structure of P2Y receptors. *Neuropharmacology* **104**: 50-61 [PMID:26519900]
# Parathyroid hormone receptors

G protein-coupled receptors → Parathyroid hormone receptors

**Overview:** The parathyroid hormone receptors (nomenclature as agreed by the **NC-IUPHAR Subcommittee on Parathyroid Hormone Receptors [662]**)) are family B G protein-coupled receptors. The parathyroid hormone (PTH)/parathyroid hormone-related peptide (PTHrP) receptor (PTH1 receptor) is activated by precursor-derived peptides: PTH (PTH, P01270) (84 amino acids), and PTHrP (PTHLH, P12272) (141 amino-acids) and related peptides (PTH-(1-34), PTHrP-(1-36) (PTHLH, P12272)). The parathyroid hormone 2 receptor (PTH2 receptor) is activated by the precursor-derived peptide TIP39 (PTH2, Q96A98) (39 amino acids). [¹²⁵I]PTH may be used to label both PTH1 and PTH2 receptors.

<table><tr><td>Nomenclature</td><td>PTH1 receptor</td><td>PTH2 receptor</td></tr><tr><td>HGNC, UniProt</td><td>PTH1R, Q03431</td><td>PTH2R, P49190</td></tr><tr><td>Potency order of endogenous ligands</td><td>PTH (PTH, P01270) = PTHrP (PTHLH, P12272)</td><td>TIP39 (PTH2, Q96A98), PTH (PTH, P01270) &gt;&gt; PTHrP (PTHLH, P12272)</td></tr><tr><td>Agonists</td><td>teriparatide [660]</td><td>TIP39 (PTH2, Q96A98) [725, 887]</td></tr><tr><td>Selective agonists</td><td>PTHrP-(1-34) (human) [661] – Rat</td><td>–</td></tr></table>

**Comments:** The parathyroid hormone type 1 receptor (PTHR) is the canonical GPCR for PTH and PTHrP. It is coupled to Gs and Gq and regulates the development of bone, heart, mammary glands and other tissues in response to PTHrP, and blood concentrations of calcium and phosphate ions, as well as vitamin D, in response to PTH. Another important action of the PTH/PTHR system is to stimulate bone formation when the hormone is intermittently administrated (daily injection).

Although PTH (PTH, P01270) is an agonist at human PTH2 receptors, it fails to activate the rodent orthologues. TIP39 (PTH2, Q96A98) is a weak antagonist at PTH1 receptors [1018].

## Further reading on Parathyroid hormone receptors

* Cheloha RW et al. (2015) PTH receptor-1 signalling-mechanistic insights and therapeutic prospects. *Nat Rev Endocrinol* **11**: 712-24 [PMID:26303600]

* Gardella TJ et al. (2015) International Union of Basic and Clinical Pharmacology. XCIII. The Parathyroid Hormone Receptors-Family B G Protein-Coupled Receptors. *Pharmacol. Rev.* **67**: 310-37 [PMID:25713287]

* Vilardaga JP et al. (2014) Endosomal generation of cAMP in GPCR signaling. *Nat. Chem. Biol.* **10**: 700-6 [PMID:25271346]
# Platelet-activating factor receptor

G protein-coupled receptors → Platelet-activating factor receptor

**Overview:** Platelet-activating factor (PAF, 1-O-alkyl-2-acetyl-sn-glycero-3-phosphocholine) is an ether phospholipid mediator associated with platelet coagulation, but also subserves inflammatory roles. The PAF receptor (**provisional nomenclature recommended by NC-IUPHAR [612]**) is activated by PAF and other suggested endogenous ligands are oxidized phosphatidylcholine [1378] and lysophosphatidylcholine [1615]. It may also be activated by bacterial lipopolysaccharide [1540].

<table><tr><td>Nomenclature</td><td>PAF receptor</td></tr><tr><td>HGNC, UniProt</td><td>PTAFR, P25105</td></tr><tr><td>Selective agonists</td><td>methylcarbamyl PAF</td></tr><tr><td>Selective antagonists</td><td>foropafant (pK<sub>i</sub> 10.3) [853], ABT-491 (pK<sub>i</sub> 9.2) [32], CV-6209 (pIC<sub>50</sub> 8.1–8.3) [716, 1539], L659989 (pK<sub>i</sub> 7.8) [937], apafant (pK<sub>i</sub> 5.2–7.5) [1654, 2067]</td></tr><tr><td>Labelled ligands</td><td>[<sup>3</sup>H]PAF (Agonist) [640, 1539]</td></tr></table>

**Comments:** Note that a previously recommended radioligand ([³H]apafant; K<sub>d</sub> 44.6 nM) is currently unavailable.

## Further reading on Platelet-activating factor receptor

Foord SM *et al.* (2005) International Union of Pharmacology. XLVI. G protein-coupled receptor list. *Pharmacol Rev* **57**: 279-288 [PMID:15914470]

Ishii S *et al.* (2000) Platelet-activating factor (PAF) receptor and genetically engineered PAF receptor mutant mice. *Prog. Lipid Res.* **39**: 41-82 [PMID:10729607]

Prescott SM *et al.* (2000) Platelet-activating factor and related lipid mediators. *Annu. Rev. Biochem.* **69**: 419-45 [PMID:10966465]
# Prokineticin receptors

G protein-coupled receptors → Prokineticin receptors

**Overview:** Prokineticin receptors, PKR₁ and PKR₂ (**provisi**onal **nomenclature as recommended by NC-IUPHAR** [612]) respond to the cysteine-rich 81-86 amino-acid peptides prokineticin-1 (**PROK1**, Q9HC23) (also known as endocrine gland-derived vascular endothelial growth factor, mambakine) and

prokineticin-2 (**PROK2**, Q9HC23) (protein Bv8 homologue). An orthologue of PROK1 from black mamba (*Dendroaspis polylepis*) venom, mamba intestinal toxin 1 (MIT1, [1905]) is a potent, non-selective agonist at prokineticin receptors [1393], while Bv8, an orthologue of PROK2 from amphibians (*Bombina sp.*, [1474]), is

equipotent at recombinant PKR₁ and PKR₂ [1559], and has high potency in macrophage chemotaxis assays, which are lost in PKR₁-null mice.

<table><tr><td>Nomenclature</td><td>PKR<sub>1</sub></td><td>PKR<sub>2</sub></td></tr><tr><td>HGNC, UniProt</td><td>PROKR1, Q8TCW9</td><td>PROKR2, Q8NFJ6</td></tr><tr><td>Potency order of endogenous ligands</td><td>prokineticin-2 (PROK2, Q9HC23) > prokineticin-1 (PROK1, Q9HC23) > prokineticin-2β (PROK2) [348, 1285, 1393, 2005]</td><td>prokineticin-2 (PROK2, Q9HC23) > prokineticin-1 (PROK1, Q9HC23) > prokineticin-2β (PROK2) [348, 1285, 1393, 2005]</td></tr><tr><td>Agonists</td><td>MIT1 [1393]</td><td>MIT1 [1393]</td></tr><tr><td>Selective agonists</td><td>IS20 [668], IS1 [668]</td><td>—</td></tr><tr><td>Labelled ligands</td><td>[125I]BH-MIT1 (Agonist) [1393]</td><td>[125I]BH-MIT1 (Agonist) [1393]</td></tr></table>

**Comments:** Genetic mutations in *PROKR1* are associated with Hirschsprung's disease [1836], while genetic mutations in *PROKR2* are associated with hypogonadotropic hypogonadism with anosmia [504], hypopituitarism with pituitary stalk interruption [1792] and Hirschsprung's disease [1836]. PKR₂ has been recently identified as a receptor for *T. cruzi* natural infection [1077].

## Further reading on Prokineticin receptors

* Boulberdaa M *et al.* (2011) Prokineticin receptor 1 (PKR1) signalling in cardiovascular and kidney functions. *Cardiovasc. Res.* **92**: 191-8 [PMID:21856786]

* Negri L *et al.* (2018) The Prokineticins: Neuromodulators and Mediators of Inflammation and Myeloid Cell-Dependent Angiogenesis. *Physiol. Rev.* **98**: 1055-1082 [PMID:29537336]

* Negri L *et al.* (2012) Bv8/PK2 and prokineticin receptors: a druggable pronociceptive system. *Curr Opin Pharmacol* **12**: 62-6 [PMID:22136937]

* Negri L *et al.* (2007) Bv8/Prokineticin proteins and their receptors. *Life Sci.* **81**: 1103-16 [PMID:17881008]

* Ngan ES *et al.* (2008) Prokineticin-signaling pathway. *Int. J. Biochem. Cell Biol.* **40**: 1679-84 [PMID:18440852]
# Prolactin-releasing peptide receptor

G protein-coupled receptors → Prolactin-releasing peptide receptor

**Overview:** The precursor (PRLH, P81277) for PrRP generates 31 and 20-amino-acid versions. QRFP43 (QRFP, P83859) (named after a pyroglutamylated arginine-phenylalanine-amide peptide) is a 43 amino acid peptide derived from QRFP (P83859) and is

also known as P518 or 26RFa. RFRP is an RF amide-related peptide [875] derived from a FMRFamide-related peptide precursor (NPVF, Q9HCQ7), which is cleaved to generate neuropeptide SF (NPFF, O15130), neuropeptide RFRP-1 (NPVF, Q9HCQ7), neu-

ropeptide RFRP-2 (NPVF, Q9HCQ7) and neuropeptide RFRP-3 (NPVF, Q9HCQ7) (neuropeptide NPVF).

Nomenclature PrRP receptor

HGNC, UniProt PRLHR, P49683

Potency order of endogenous ligands PrRP-20 (PRLH, P81277) = PrRP-31 (PRLH, P81277) [1201]

Endogenous agonists PrRP-20 (PRLH, P81277) [561, 1201], PrRP-31 (PRLH, P81277) [561, 1201]

Endogenous antagonists neuropeptide Y (NPY, P01303) (pKᵢ 5.4) [1190]

Labelled ligands [¹²⁵I]PrRP-20 (human) (Agonist) [1201], [¹²⁵I]PrRP31 (Agonist) [552]

**Comments:** The orphan receptor GPR83 (Q9NYM4) shows sequence similarities with NPFF1, NPFF2, PrRP and QRFP receptors.

## Further reading on Prolactin-releasing peptide receptor

Samson WK *et al*. (2006) Prolactin releasing peptide (PrRP): an endogenous regulator of cell growth. *Peptides* **27**: 1099-103 [PMID:16500730]

Takayanagi Y *et al*. (2010) Roles of prolactin-releasing peptide and RFamide related peptides in the control of stress and food intake. *FEBS J.* **277**: 4998-5005 [PMID:21126313]
# Prostanoid receptors

G protein-coupled receptors → Prostanoid receptors

**Overview:** Prostanoid receptors (nomenclature as agreed by the **NC-IUPHAR Subcommittee on Prostanoid Receptors [2329]**)) are activated by the endogenous ligands prostaglandins PGD₂, PGE₁, PGE₂, PGF₂α, PGH₂, prostacyclin [PGI₂] and thromboxane A₂. Measurement of the potency of PGI₂ and thromboxane A₂ is hampered by their instability in physiological salt solution; they are often replaced by cicaprost and U46619, respectively, in receptor characterization studies.

<table><tr><td>Nomenclature</td><td>DP₁ receptor</td><td>DP₂ receptor</td></tr><tr><td>HGNC, UniProt</td><td>PTGDR, Q13258</td><td>PTGDR2, Q9Y5Y4</td></tr><tr><td>Potency order of endogenous ligands</td><td>PGD₂ > PGE₁ > PGE₂ > PGF₂α > PGI₂, thromboxane A₂</td><td>PGD₂ > PGF₂α, PGE₂ > PGI₂, thromboxane A₂</td></tr><tr><td>Agonists</td><td>treprostinil [2071, 2300]</td><td>—</td></tr><tr><td>Selective agonists</td><td>BW 245C [188, 2330, 2331], L-644,698 [2330, 2331]</td><td>15(R)-15-methyl-PGD₂ [821, 1484, 2052]</td></tr><tr><td>Antagonists</td><td>—</td><td>fevipiprant (pK<sub>d</sub> 9) [2072, 2073], ramatroban (pK<sub>i</sub> 7.4) [2052]</td></tr><tr><td>Selective antagonists</td><td>laropiprant (pK<sub>i</sub> 10.1) [2046], BWA868C (pK<sub>i</sub> 8.6–9.3) [188, 701, 2330], ONO-AE3-237 (pK<sub>i</sub> 7.7) [877, 2144, 2146]</td><td>CAY 10471 (pI<sub>C₅₀</sub> 8.9) [1832, 2174]</td></tr><tr><td>Labelled ligands</td><td>[³H]PGD₂ (Agonist) [2314, 2330]</td><td>[³H]PGD₂ (Agonist) [1394, 1949]</td></tr></table>

<table><tr><td>Nomenclature</td><td>EP₁ receptor</td><td>EP₂ receptor</td><td>EP₃ receptor</td><td>EP₄ receptor</td></tr><tr><td>HGNC, UniProt</td><td>PTGER1, P34995</td><td>PTGER2, P43116</td><td>PTGER3, P43115</td><td>PTGER4, P35408</td></tr><tr><td>Potency order of endogenous ligands</td><td>PGE₂ > PGE₁ > PGF₂α, PGI₂ > PGD₂, thromboxane A₂</td><td>PGE₂ = PGE₁ > PGF₂α, PGI₂ > PGD₂, thromboxane A₂</td><td>PGE₂, PGE₁ > PGF₂α, PGI₂ > PGD₂, thromboxane A₂</td><td>PGE₂ = PGE₁ > PGF₂α, PGI₂ > PGD₂, thromboxane A₂</td></tr><tr><td>Endogenous agonists</td><td>—</td><td>PGE₂ [7, 2034, 2314]</td><td>PGE₂ (EP₃-III isoform) [7]</td><td>—</td></tr><tr><td>Agonists</td><td>17-phenyl-ω-trinor-PGE₂ [1940]</td><td>treprostinil [2071, 2300], PGE₁ [119]</td><td>misoprostol (methyl ester) (EP₃-III isoform) [7]</td><td>17-phenyl-ω-trinor-PGE₂ [2113]</td></tr><tr><td>Selective agonists</td><td>ONO-DI-004 [2062] – Mouse</td><td>ONO-AE1-259 [2062] – Mouse, omidenepag [1103], butaprost (free acid form) [7, 2034]</td><td>sulprostone (EP₃-III isoform) [7], ONO-AE-248 [617, 1315]</td><td>L902688 [618, 1235], ONO-AE1-329 [617, 618]</td></tr><tr><td>Antagonists</td><td>—</td><td>—</td><td>—</td><td>EP₄A (pK<sub>i</sub> 7.6–8.5) [1340, 2406]</td></tr><tr><td>Selective antagonists</td><td>ONO-8711 (pK<sub>i</sub> 9.2) [2269], SC-51322 (pK<sub>i</sub> 7.9) [7]</td><td>PF-04418948 (PF-04418948 has weaker affinity at the EP₂-receptor in guinea-pigs) (pK<sub>B</sub> 8.3) [14, 169], TG6-129 (pK<sub>B</sub> 8.1) [654]</td><td>L-826266 (EP₃-III isoform (pK<sub>i</sub>=8.04 in the presence of HSA)) (pK<sub>i</sub> 9.1) [1026], ONO-AE3-240 (pI<sub>C₅₀</sub> 8.8) [42] – Mouse, DG-041 (pK<sub>i</sub> 8.4) [1024]</td><td>ONO-AE3-208 (pK<sub>i</sub> 8.5), GW 627368 (pK<sub>i</sub> 7–7.1) [2314, 2315]</td></tr><tr><td>Labelled ligands</td><td>[³H]PGE₂ (Agonist) [7, 1940, 2314]</td><td>[³H]PGE₂ (Agonist) [7, 2314]</td><td>[³H]PGE₂ (Agonist) [7, 2314]</td><td>[³H]PGE₂ (Agonist) [7, 461, 2300, 2314]</td></tr></table>
<table><tr><td>Nomenclature</td><td>FP receptor</td><td>IP receptor</td><td>TP receptor</td></tr><tr><td>HGNC, UniProt</td><td>PTGFR, P43088</td><td>PTGIR, P43119</td><td>TBXA2R, P21731</td></tr><tr><td>Potency order of endogenous ligands</td><td>PGF2α > PGD2 > PGE2 > PGI2, thromboxane A2</td><td>PGI2 > PGE1 > PGD2, PGF2α > thromboxane A2</td><td>thromboxane A2 = PGH2 > PGD2, PGE2, PGF2α, PGI2</td></tr><tr><td>Endogenous agonists</td><td>–</td><td>PGI2 [1965], PGE1 [1391, 2036]</td><td>–</td></tr><tr><td>Agonists</td><td>ONO-9054 [2366]</td><td>iloprost [7, 2314], treprostinil [2300]</td><td>–</td></tr><tr><td>Selective agonists</td><td>fluprostenol [7], latanoprost (free acid form) [7]</td><td>cicaprost [7], MRE-269 [145, 1181]</td><td>U46619 [7]</td></tr><tr><td>Antagonists</td><td>–</td><td>–</td><td>ramatroban (pK<sub>i</sub> 8) [2114]</td></tr><tr><td>Selective antagonists</td><td>AS604872 (pK<sub>i</sub> 7.5) [397]</td><td>RO1138452 (pK<sub>i</sub> 8.7) [176], RO3244794 (pA<sub>2</sub> 8.5) [176]</td><td>vapiprost (pK<sub>i</sub> 8.3–9.4) [69, 1326], SQ-29548 (pK<sub>i</sub> 8.1–9.1) [7, 2070, 2314]</td></tr><tr><td>Labelled ligands</td><td>[<sup>3</sup>H]PGF<sub>2α</sub> (Agonist) [7, 8, 2314], [<sup>3</sup>H](+)-fluprostenol (Agonist)</td><td>[<sup>3</sup>H]iloprost (Agonist) [7, 187, 2300, 2314]</td><td>[<sup>125</sup>I]SAP (Antagonist) (pK<sub>d</sub> 7.7–9.3) [1538], [<sup>125</sup>I]BOP (Agonist) [1500], [<sup>3</sup>H]SQ-29548 (Antagonist) (pK<sub>d</sub> 7.4–8.2) [7, 2314]</td></tr></table>

**Comments:** Whilst *cicaprost* is selective for IP receptors, it does exhibit moderate agonist potency at EP₄ receptors [7]. Apart from IP receptors, *iloprost* also binds to EP₁ receptors.

The EP₁ agonist 17-phenyl-ω-trinor-PGE₂ also shows agonist activity at EP₃ and EP₄ receptors [617, 2113]. Butaprost and SC46275 may require de-esterification within tissues to attain full agonist potency. There is evidence for subtypes of FP [1281] and TP receptors [1151, 1779]. mRNA for the EP₃ receptor undergoes alternative splicing to produce variants which can interfere with signalling [1632] or generate complex patterns of G-protein (Gᵢ/₀, Gq/₁₁, Gs and G₁₂,₁₃) coupling (e.g. [1143, 1557]). The number of

EP₃ receptor (protein) variants are variable depending on species, with five in human, three in rat and three in mouse. Putative receptor(s) for prostamide F (which as yet lack molecular correlates) and which preferentially recognize PGF2-1-ethanolamide and its analogues (e.g. Bimatoprost) have been identified, together with moderate-potency antagonists (e.g. AGN 211334) [2328].

The free acid form of AL-12182, AL12180, used in *in vitro* studies, has a EC₅₀ of 15nM which is the concentration of the compound giving half-maximal stimulation of inositol phosphate turnover in HEK-293 cells expressing the human FP receptor [1941].

References given alongside the TP receptor agonists I-BOP [1409] and STA₂ [69] use human platelets as the source of TP receptors for competition radio-ligand binding assays to determine the indicated activity values.

Pharmacological evidence for a second IP receptor, denoted IP₂, in the central nervous system [2091, 2272] and in the BEAS-2B human airway epithelial cell line [2317] is available. This receptor is selectively activated by 15R-17,18,19,20-tetranor-16-m-tolyl-isocarbacyclin (15R-TIC) and 15R-Deoxy 17,18,19,20-tetranor-16-m-tolyl-isocarbacyclin (15-deoxy-TIC). However, molecular biological evidence for an IP₂ subtype is currently lacking.

## Further reading on Prostanoid receptors

Woodward DF *et al.* (2011) International union of basic and clinical pharmacology. LXXXIII: classification of prostanoid receptors, updating 15 years of progress. *Pharmacol. Rev.* **63**: 471-538 [PMID:21752876]
# Proteinase-activated receptors

G protein-coupled receptors → Proteinase-activated receptors

**Overview:** Proteinase-activated receptors (PARs, **nomenclature as agreed by the NC-IUPHAR Subcommittee on Proteinase-activated Receptors [894]**)) are unique members of the GPCR superfamily activated by proteolytic cleavage of their amino terminal exodomains. Agonist proteinase-induced hydrolysis unmasks a tethered ligand (TL) at the exposed amino terminus, which acts intramolecularly at the binding site in the body of the receptor to effect transmembrane signalling. TL sequences

at human PAR1-4 are SFLLRN-NH₂, SLIGKV-NH₂, TFRGAP-NH₂ and GYPGQV-NH₂, respectively. With the exception of PAR3, synthetic peptides with these sequences (as carboxyl terminal amides) are able to act as agonists at their respective receptors. Several proteinases, including neutrophil elastase, cathepsin G and chymotrypsin can have inhibitory effects at PAR1 and PAR2 such that they cleave the exodomain of the receptor without inducing activation of Gαq-coupled calcium signalling, thereby preventing

activation by activating proteinases but not by agonist peptides. Neutrophil elastase (NE) cleavage of PAR1 and PAR2 can however activate MAP kinase signaling by exposing a TL that is different from the one revealed by trypsin [1764]. PAR2 activation by NE regulates inflammation and pain responses [1518, 2431] and triggers mucin secretion from airway epithelial cells [2434].

<table><thead><tr><th></th><th>PAR1</th><th>PAR2</th><th>PAR3</th><th>PAR4</th></tr></thead><tbody><tr><td>Nomenclature</td><td>PAR1</td><td>PAR2</td><td></td><td></td></tr><tr><td>HGNC, UniProt</td><td>F2R, P25116</td><td>F2RL1, P55085</td><td>F2RL2, O00254</td><td>F2RL3, Q96RI0</td></tr><tr><td>Agonist proteases</td><td>thrombin (F2, P00734), activated protein C (PROC, P04070), matrix metalloproteinase 1 (MMP1, P45452), matrix metalloproteinase 13 (MMP13, P45452) [81]</td><td>Trypsin, tryptase, TF/VIIa, Xa; elastase, neutrophil expressed; cathepsin S [1001, 1762]</td><td>thrombin (F2, P00734)</td><td>thrombin (F2, P00734), trypsin, cathepsin G (CTSG, P08311)</td></tr><tr><td>Agonists</td><td>F16357</td><td>–</td><td>–</td><td>–</td></tr><tr><td>Selective agonists</td><td>TFLLR-NH₂ [391]</td><td>AY77 [2385], GB110 [112], 2-furoyl-LIGRL-O-amide [1419], SLIGKV-NH₂ [1241], SLIGRL-NH₂ [1241]</td><td>–</td><td>AYPGKF-NH₂, GYPGKF-NH₂, GYPGQV-NH₂</td></tr><tr><td>Selective antagonists</td><td>vorapaxar (pKᵢ 8.1) [327], atopaxar (pIC₅₀ 7.7) [1124], RWJ-56110 (pIC₅₀ 6.4) [52]</td><td>I-191 (pIC₅₀ 7.1) [1000], AZ8838 (pK₉ 6.5) [360], GB88 (pIC₅₀ 5.7) [2050], P2pal18s [1933]</td><td>–</td><td>BMS-986120 (pK₉ 10) [2325], YD-3 (pIC₅₀ 6.9) [2283], ML354 (pIC₅₀ 6.8) [2283], P4pal-10 [427], RAG8 (Agonist) [1763]</td></tr><tr><td>Allosteric modulators</td><td>–</td><td>AZ3451 (Negative) (pIC₅₀ 7.6) [360]</td><td>–</td><td>–</td></tr><tr><td>Labelled ligands</td><td>[³H]haTRAP (Agonist) [19]</td><td>2-furoyl-LIGRL[N-(Alexa Fluor 594)-O]-NH₂ (Agonist) [895], 2-furoyl-LIGRL[N[³H]propionyl]-O-NH₂ (Agonist) [895], [³H]2-furoyl-LIGRL-NH₂ (Selective Agonist) [1040], trans-cinnamoyl-LIGRL-O-[N-[³H]propionyl]-NH₂ (Agonist) [30]</td><td>–</td><td>–</td></tr><tr><td>Comments</td><td>TFLLR-NH₂ is selective relative to the PAR₂ receptor [171, 1053].</td><td>2-Furoyl-LIGRL-O-NH₂ activity was measured via calcium mobilisation in HEK 293 cells which constitutively coexpress human PAR₁ and PAR₂.</td><td>–</td><td>–</td></tr></tbody></table>

**Comments:** Endogenous serine proteases (EC 3.4.21.) active at the proteinase-activated receptors include: thrombin (F2, P00734), generated by the action of Factor X (F10, P00742) on liver-derived prothrombin (F2, P00734); trypsin, generated by the

action of enterokinase (TMPRSS1, P98073) on pancreatic-derived trypsinogen (PRSS1, P07477); tryptase, a family of enzymes (α/β1, TPSAB1, Q15661; γ1 TPSG1, Q9NRR2; δ1 TPSD1, Q9BZJ3) secreted from mast cells; cathepsin G (CTSG, P08311) generated from

leukocytes; liver-derived protein C (PROC, P04070) generated in plasma by thrombin (F2, P00734) and matrix metalloproteinase 1 (MMP1, P45452).
Further reading on Proteinase-activated receptors

Adams MN *et al.* (2011) Structure, function and pathophysiology of protease activated receptors. *Pharmacol. Ther.* **130**: 248-82 [PMID:21277892]

Canto I *et al.* (2012) Allosteric modulation of protease-activated receptor signaling. *Mini Rev Med Chem* **12**: 804-11 [PMID:22681248]

García PS *et al.* (2010) The role of thrombin and protease-activated receptors in pain mechanisms. *Thromb. Haemost.* **103**: 1145-51 [PMID:20431855]

Hollenberg MD *et al.* (2002) International Union of Pharmacology. XXVIII. Proteinase-activated receptors. *Pharmacol. Rev.* **54**: 203-17 [PMID:12037136]

Ramachandran R *et al.* (2012) Targeting proteinase-activated receptors: therapeutic potential and challenges. *Nat Rev Drug Discov* **11**: 69-86 [PMID:22212680]

Soh UJ *et al.* (2010) Signal transduction by protease-activated receptors. *Br. J. Pharmacol.* **160**: 191-203 [PMID:20423334]

QRFP receptor

G protein-coupled receptors → QRFP receptor

**Overview:** The human gene encoding the QRFP receptor (nomenclature as agreed by the **NC-IUPHAR Subcommittee on the QRFP receptor [1259]**; QRFPR, formerly known as the Peptide P518 receptor), previously designated as an orphan GPCR receptor was identified in 2001 by Lee *et al.* from a hy-

pothalamus cDNA library [1237]. However, the reported cDNA (AF411117) is a chimera with bases 1-127 derived from chromosome 1 and bases 155-1368 derived from chromosome 4. When corrected, QRFPR (also referred to as SP9155 or AQ27) encodes a 431 amino acid protein that shares sequence similarities in the

transmembrane spanning regions with other peptide receptors. These include neuropeptide FF2 (38%), neuropeptide Y₂ (37%) and galanin Gal₁ (35%) receptors.

<table><tr><td>Nomenclature</td><td>QRFP receptor</td></tr><tr><td>HGNC, UniProt</td><td>QRFPR, Q96P65</td></tr><tr><td>Endogenous agonists</td><td>QRFP26 (QRFP) [343, 999]</td></tr><tr><td>Agonists</td><td>LV-2186 [41], LV-2172 [1572]</td></tr><tr><td>Selective antagonists</td><td>compound 25e (pIC<sub>50</sub> 7.3) [687, 688]</td></tr><tr><td>Labelled ligands</td><td>[<sup>125</sup>I]QRFP43 (human) (Agonist) [641, 1164, 2090], [<sup>125</sup>I]26RFa (human) (Agonist) [260]</td></tr></table>

**Comments:** The orphan receptor *GPR83* (9NYM4) shows sequence similarities with the QRFP receptor, as well as with the NPFF1, NPFF2, and PrRP receptors.

Further reading on QRFP receptor

Chartrel N *et al.* (2011) The RFamide neuropeptide 26RFa and its role in the control of neuroendocrine functions. *Front Neuroendocrinol* **32**: 387-97 [PMID:21530572]

Fukusumi S *et al.* (2006) Recent advances in mammalian RFamide peptides: the discovery and functional analyses of PrRP, RFRPs and QRFP. *Peptides* **27**: 1073-86 [PMID:16500002]

Leprince J *et al.* (2017) The Arg-Phe-amide peptide 26RFa/glutamine RF-amide peptide and its receptor: IUPHAR Review 24. *Br. J. Pharmacol.* **174**: 3573-3607 [PMID:28613412]
# Relaxin family peptide receptors

G protein-coupled receptors → Relaxin family peptide receptors

**Overview:** Relaxin family peptide receptors (RXFP, nomenclature as agreed by the NC-IUPHAR Subcommittee on Relaxin family peptide receptors [120, 785]) may be divided into two pairs, RXFP1/2 and RXFP3/4. Endogenous agonists at these receptors are heterodimeric peptide hormones structurally related to insulin: relaxin-1 (RLN1, P04808), relaxin (RLN2, P04090), relaxin-3 (RLN3, Q8WXF3) (also known as INSL7), insulin-like peptide 3 (INSL3 (INSL3, P51460)) and INSL5 (INSL5, Q9Y5Q6). Species homologues of relaxin have distinct pharmacology and relaxin (RLN2, P04090) interacts with RXFP1, RXFP2 and RXFP3, whereas mouse and rat relaxin selectively bind to and activate RXFP1 [1912]. Relaxin-3 (RLN3, Q8WXF3) is the ligand for RXFP3 but it also binds to RXFP1 and RXFP4 and has differential affinity for RXFP2 between species [1911]. INSL5 (INSL5, Q9Y5Q6) is the ligand for RXFP4 but is a weak antagonist of RXFP3. Relaxin (RLN2, P04090) and INSL3 (INSL3, P51460) have

multiple complex binding interactions with RXFP1 [1930] and RXFP2 [886] which direct the N-terminal LDLa modules of the receptors together with a linker domain to act as a tethered ligand and to direct receptor signaling [1913]. INSL5 (INSL5, Q9Y5Q6) and relaxin-3 (RLN3, Q8WXF3) interact with their receptors using distinct residues in their B-chains for binding, and activation, respectively [921, 2324].

<table><tr><td>Nomenclature</td><td>RXFP1</td><td>RXFP2</td><td>RXFP3</td><td>RXFP4</td></tr><tr><td>HGNC, UniProt</td><td>RXFP1, Q9HBX9</td><td>RXFP2, Q8WXD0</td><td>RXFP3, Q9NSD7</td><td>RXFP4, Q8TDU9</td></tr><tr><td>Potency order of endogenous ligands</td><td>relaxin (RLN2, P04090) = relaxin-1 (RLN1, P04808) &gt; relaxin-3 (RLN3, Q8WXF3) [2049]</td><td>INSL3 (INSL3, P51460) &gt; relaxin (RLN2, P04090) &gt;&gt; relaxin-3 (RLN3, Q8WXF3) [1174, 2049]</td><td>relaxin-3 (RLN3, Q8WXF3) &gt; relaxin-3 (B chain) (RLN3, Q8WXF3) &gt; relaxin (RLN2, P04090) [1296]<br>INSL5 (INSL5, Q9Y5Q6) (pK<sub>i</sub> 7) [2438]</td><td>INSL5 (INSL5, Q9Y5Q6) = relaxin-3 (RLN3, Q8WXF3) &gt; relaxin-3 (B chain) (RLN3, Q8WXF3) [1294, 1295]</td></tr><tr><td>Endogenous antagonists</td><td>–</td><td>–</td><td>–</td><td>–</td></tr><tr><td>Antagonists</td><td>B-R13/17K H2 relaxin (pEC<sub>50</sub> 5.7–6.7) [913, 1570]</td><td>–</td><td>R3(BΔ23-27)R/15 chimeric peptide (pIC<sub>50</sub> 9.2) [1165]</td><td>R3(BΔ23-27)R/15 chimeric peptide (pIC<sub>50</sub> 8–8.6) [823, 1165]</td></tr><tr><td>Selective antagonists</td><td>–</td><td>A(9-26)INSL3 (pK<sub>i</sub> 9.1) [912], A(10-24)INSL3 (pK<sub>i</sub> 8.7) [912], A(C10/15S)INSL3 (pK<sub>i</sub> 8.6) [2422], INSL3 B chain dimer analogue 8 (pK<sub>i</sub> 8.5) [1938], A(Δ10/15C)INSL3 (pK<sub>i</sub> 8.3) [2422], cyclic INSL3 B-chain analogue 6 (pK<sub>i</sub> 6.7) [1936], INSL3 B-chain analogue (pK<sub>i</sub> 5.1) [479], (des 1-8) A-chain INSL3 analogue [285]</td><td>minimised relaxin-3 analogue 3 (pK<sub>i</sub> 7.6) [1934], R3-B1-22R (pK<sub>i</sub> 7.4) [823]</td><td>minimised relaxin-3 analogue 3 (pIC<sub>50</sub> 6.6) [1934]</td></tr><tr><td>Allosteric modulators</td><td>ML290 (Agonist) (pEC<sub>50</sub> 7) [2346, 2349]</td><td>–</td><td>–</td><td>–</td></tr><tr><td>Labelled ligands</td><td>[³³P]relaxin (human) (Agonist) [786, 2049], europium-labelled relaxin (Agonist) [1935], [¹²⁵I]relaxin (human) (Agonist)</td><td>[¹²⁵I]INSL3 (human) (Agonist) [1516], [³³P]relaxin (human) (Agonist) [786, 2049]</td><td>[¹²⁵I]relaxin-3 (human) (Agonist) [1296], [¹²⁵I]relaxin-3-B/INSL5 A chimera (Agonist) [1294], europium-labelled relaxin-3-B/INSL5 A chimera (Agonist) [823]</td><td>[¹²⁵I]relaxin-3 (human) (Agonist) [1295], [¹²⁵I]relaxin-3-B/INSL5 A chimera (Agonist) [1294], europium-labelled mouse INSL5 (Agonist) [135], europium-labelled relaxin-3-B/INSL5 A chimera (Agonist) [823], europium-labelled INSL5 (pK<sub>d</sub> 8.3) [823]</td></tr><tr><td>Comments</td><td>–</td><td>Europium-labelled INSL3 is a fluorescent ligand for this receptor (K<sub>d</sub>=1nM) [1937].</td><td>–</td><td>–</td></tr></table>
**Comments:** Relaxin (RLN2, P04090) is the cognate peptide ligand and for RXFP1 and is in extended Phase III clinical trials for the treatment of acute heart failure [1435]. Relaxin has vasodilatory, anti-fibrotic, angiogenic, anti-apoptotic and anti-inflammatory effects. A small molecule allosteric agonists ML290 has been developed [1944, 2349], and a relaxin B-chain mimetic peptide B7-33 has been developed which that has cell specific signaling properties [911]. The antifibrotic actions of relaxin are dependent on the angiotensin receptor AT₂ [377]. INSL3 (INSL3, P51460) is the cognate peptide for RXFP2 and is a circulating hormone that in males is essential for testicular descent in utero [1556] and in females has important roles in ovarian follicle function [961]. In adults, INSL3

has potential roles in testicular function [962] and the musculo-skeletal system [472]. RXFP2 is also present in brain, associated with cortico-thalamic motor circuits [1917]. cAMP elevation is the major signalling pathway for both RXFP1 and RXFP2 [919, 920], but RXFP1 also activates MAP kinases, nitric oxide signalling, and tyrosine kinase phosphorylation; and relaxin can interact with glucocorticoid receptors [787]. Receptor expression profiles suggest that RXFP3 is a brain neuropeptide receptor and RXFP4 a gut hormone receptor. The brain relaxin-3/RXFP3 system modulates feeding [652, 653, 823, 1934, 1992] via effects in hypothalamus [475, 652, 1039], anxiety [1842, 2415], reward and motivated, goal-directed behaviours [906, 1842, 2239], and spatial and social

memory [34, 780]. Of the other relaxin peptides, relaxin-3 (RLN3, Q8WXF3) is an agonist at RXFP3 and RXFP4 whereas INSL5 (INSL5, Q9Y5Q6) is an agonist at RXFP4 and a weak antagonist at RXFP3. INSL5 (INSL5, Q9Y5Q6) is secreted from enteroendocrine L cells and the INSL5/RXFP4 system affects food intake [751] and glucose homeostasis [1331]. RXFP3 and RXFP4 couple to G₁/o and inhibit adenylyl cyclase [1296, 2191], and also cause Erk1/2 phosphorylation [2191]. RXFP4 also causes phosphorylation of p38MAPK, Akt and S6RP [55] and GLP-1 secretion in vitro [54]. There is evidence that at RXFP3, relaxin (RLN2, P04090) is a biased ligand compared to the cognate ligand relaxin-3 (RLN3, Q8WXF3) [2191].

Further reading on Relaxin family peptide receptors

Bathgate RA *et al*. (2013) Relaxin family peptides and their receptors. *Physiol. Rev.* **93**: 405-80 [PMID:23303914]

Du XJ *et al*. (2010) Cardiovascular effects of relaxin: from basic science to clinical therapy. *Nat Rev Cardiol* **7**: 48-58 [PMID:19935741]

Halls ML *et al*. (2015) International Union of Basic and Clinical Pharmacology. XCV. Recent advances in the understanding of the pharmacology and biological roles of relaxin family peptide receptors 1-4, the receptors for relaxin family peptides. *Pharmacol. Rev.* **67**: 389-440 [PMID:25761609]

Ivell R *et al*. (2011) Relaxin family peptides in the male reproductive system–a critical appraisal. *Mol. Hum. Reprod.* **17**: 71-84 [PMID:20952422]
# Somatostatin receptors

G protein-coupled receptors → Somatostatin receptors

**Overview:** Somatostatin (somatotropin release inhibiting factor) is an abundant neuropeptide, which acts on five subtypes of somatostatin receptor (SST₁-SST₅; **nomenclature as agreed by the NC-IUPHAR Subcommittee on Somatostatin Receptors [773]**). Activation of these receptors produces a wide range of physiological effects throughout the body including the inhibition of secretion of many hormones. Endogenous ligands for these receptors are somatostatin-14 (SRIF-14 (SST, P61278)) and somatostatin-28 (SRIF-28 (SST, P61278)). Cortistatin-14 (Mouse, Rat) has also been suggested to be an endogenous ligand for somatostatin receptors [468].

<table><thead><tr><th></th><th>SST<sub>1</sub> receptor</th><th>SST<sub>2</sub> receptor</th><th>SST<sub>3</sub> receptor</th><th>SST<sub>4</sub> receptor</th><th>SST<sub>5</sub> receptor</th></tr></thead><tbody><tr><td>Nomenclature</td><td>SSTR1, P30872</td><td>SSTR2, P30874</td><td>SSTR3, P32745</td><td>SSTR4, P31391</td><td>SSTR5, P35346</td></tr><tr><td>HGNC, UniProt</td><td>pasireotide [1893]</td><td>pasireotide [1893], veldoreotide [15]</td><td>pasireotide [1893]</td><td>NNC269100 [1306], veldoreotide [15]</td><td>pasireotide [1893], veldoreotide [15]</td></tr><tr><td>Agonists</td><td>L-797,591 [1817], Des-Ala<sup>1,2,5</sup>-[D-Trp<sup>8</sup>,IAmp<sup>9</sup>]SRIF [565]</td><td>L-054,522 [2376], BIM 23027 [313], L-779,976 [1817], octreotide [257, 1666, 1966, 1967, 1968, 2376], lanreotide [257, 1666, 1966, 1967, 1968]</td><td>L-796,778 [1817]</td><td>L-803,087 [1817], J-2156 [562]</td><td>BIM 23052 [1439, 1966, 1967, 1968], L-817,818 [1817]</td></tr><tr><td>Selective agonists</td><td>SRA880 (pK<sub>d</sub> 8–8.1) [916]</td><td>DOTA-<sub>JR11</sub> [326]</td><td>MK-4256 (pIC<sub>50</sub> 9.2) [837], ACQ090 (pK<sub>i</sub> 7.9) [917]</td><td>–</td><td>S5A1 (pK<sub>i</sub> 9.3) [585]</td></tr><tr><td>Selective antagonists</td><td></td><td></td><td></td><td></td><td></td></tr></tbody></table>

**Comments:** [¹²⁵I]Tyr¹¹-SRIF-14, [¹²⁵I]LTT-SRIF-28, [¹²⁵I]CGP 23996 and [¹²⁵I]Tyr¹⁰-CST14 may be used to label somatostatin receptors nonselectively. A number of nonpeptide subtype-selective agonists have been synthesised [1817]. Octreotide and lanreotide are being used in the treatment of SST₂-expressing neuroendocrine tumors and pasireotide for SST₅-expressing neuroendocrine tumors. A novel peptide somatostatin analogue, veldoreotide (COR-005), has affinity for SST₂, SST₄ and SST₅ receptors and is a potent inhibitor of GH secretion [1717, 1954].

## Further reading on Somatostatin receptors

* Colao A *et al.* (2011) Resistance to somatostatin analogs in acromegaly. *Endocr. Rev.* **32**: 247-71 [PMID:21123741]

* Günther T *et al.* (2018) International Union of Basic and Clinical Pharmacology. CV. Somatostatin Receptors: Structure, Function, Ligands, and New Nomenclature. *Pharmacol. Rev.* **70**: 763-835 [PMID:30232095]

* Hoyer D *et al.* (2000) Somatostatin receptors. *In The IUPHAR Compendium of Receptor Characterization and Classification, 2nd edn.* Edited by Watson SP, Girdlestone D: IUPHAR Media: 354-364

* Schulz S *et al.* (2014) Fine-tuning somatostatin receptor signalling by agonist-selective phosphorylation and dephosphorylation: IUPHAR Review 5. *Br. J. Pharmacol.* **171**: 1591-9 [PMID:24328848]

* Weckbecker G *et al.* (2003) Opportunities in somatostatin research: biological, chemical and therapeutic aspects. *Nat Rev Drug Discov* **2**: 999-1017 [PMID:14654798]
# Succinate receptor

G protein-coupled receptors → Succinate receptor

**Overview:** Nomenclature as recommended by **NC-IUPHAR** [455]. The Succinate receptor has been identified as being activated by physiological levels of the Kreb's cycle intermediate succinate and other dicarboxylic acids such as maleate in 2004. Since its pairing with its endogenous ligand, the receptor has been the focus of intensive research and its role has been evidenced in various (patho)physiological processes such as regulation of renin production, retinal angiogenesis, inflammation or immune response.

<table><tr><td>Nomenclature</td><td>succinate receptor</td></tr><tr><td>HGNC, UniProt</td><td>SUCNR1, Q9BXA5</td></tr><tr><td>Endogenous agonists</td><td>succinic acid [838, 2015], maleic acid [696]</td></tr><tr><td>Agonists</td><td>compound 31 (Partial agonist) [1791], cis-epoxysuccinic acid [2153], compound 130 (Partial agonist) [2153], cis-epoxysuccinic acid [696], maleic acid [703], maleic acid [838]</td></tr></table>

**Comments:** In humans, there is the possibility of two open-reading frames (ORFs) for *SUCNR1*, one giving a protein of 330 amino acids (AA) and the other one 334-AA. Wittenberger *et al.* [2322] noted that the 330-AA protein was more likely to be expressed given the Kozak sequence surrounding the second ATG. Some databases report *SUCNR1* as being 334-AA long.

## Further reading on Succinate receptor

* Ariza AC *et al.* (2012) The succinate receptor as a novel therapeutic target for oxidative and metabolic stress-related conditions. *Front Endocrinol (Lausanne)* **3**: 22 [PMID:22649411]

* de Castro Fonseca M *et al.* (2016) GPR91: expanding the frontiers of Krebs cycle intermediates. *Cell Commun. Signal* **14**: 3 [PMID:26759054]

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

* Grimolizzi F *et al.* (2018) Multiple faces of succinate beyond metabolism in blood. *Haematologica* **103**: 1586-1592 [PMID:29954939]
# Tachykinin receptors

G protein-coupled receptors → Tachykinin receptors

**Overview:** Tachykinin receptors (provisional nomenclature as recommended by **NC-IUPHAR** [612]) are activated by the endogenous peptides substance P (TAC1, P20366) (SP), neurokinin A (TAC1, P20366) (NKA; previously known as substance K, neurokinin α, neuromedin L), neurokinin B (TAC3, Q9UHF0) (NKB; previously known as neurokinin β, neuromedin

K), neuropeptide K (TAC1, P20366) and neuropeptide γ (TAC1, P20366) (N-terminally extended forms of neurokinin A). The neurokinins (A and B) are mammalian members of the tachykinin family, which includes peptides of mammalian and nonmammalian origin containing the consensus sequence: Phe-x-Gly-Leu-Met. Marked species differences in *in vitro* pharmacology exist for

all three receptors, in the context of nonpeptide ligands. Antagonists such as *aprepitant* and *fosaprepitant* were approved by FDA and EMA, in combination with other antiemetic agents, for the prevention of nausea and vomiting associated with emetogenic cancer chemotherapy.

<table><tr><td>Nomenclature</td><td>NK<sub>1</sub> receptor</td><td>NK<sub>2</sub> receptor</td><td>NK<sub>3</sub> receptor</td></tr><tr><td>HGNC, UniProt</td><td>TACR1, P25103</td><td>TACR2, P21452</td><td>TACR3, P29371</td></tr><tr><td>Potency order of endogenous ligands</td><td>substance P (TAC1, P20366) &gt; neurokinin A (TAC1, P20366) &gt; neurokinin B (TAC3, Q9UHF0)</td><td>neurokinin A (TAC1, P20366) &gt; neurokinin B (TAC3, Q9UHF0) &gt; substance P (TAC1, P20366)</td><td>neurokinin B (TAC3, Q9UHF0) &gt; neurokinin A (TAC1, P20366) &gt; substance P (TAC1, P20366)</td></tr><tr><td>Agonists</td><td>substance P-OMe [2130]</td><td>–</td><td>–</td></tr><tr><td>Selective agonists</td><td>[Sar<sup>9</sup>,Met(O<sub>2</sub>)<sup>11</sup>]<sup>SP</sup> [2130], septide [139, 820], [Pro<sup>9</sup>]<sup>SP</sup> [2145] – Rat</td><td>[Lys<sup>5</sup>,Me-Leu<sup>9</sup>,Nle<sup>10</sup>]<sup>NKA</sup>-(4-10) [1406] – Rat, GR64349 [476] – Rat, [βAla<sup>8</sup>]<sup>neurokinin A-(4-10)</sup> [556]</td><td>[Phe(Me)<sup>7</sup>]<sup>neurokinin B</sup> [1868, 1869], senktide [1868, 1869, 2130]</td></tr><tr><td>Antagonists</td><td>L760735 (pIC<sub>50</sub> 9.7) [815]</td><td>–</td><td>–</td></tr><tr><td>Selective antagonists</td><td>aprepitant (pK<sub>i</sub> 10.1) [781, 782], CP 99994 (pK<sub>i</sub> 9.3–9.7) [57, 1869], RP67580 (pIC<sub>50</sub> 7.7) [610]</td><td>GR94800 (pK<sub>i</sub> 9.8) [223], saredutant (pK<sub>i</sub> 9.4–9.7) [57, 556, 1869], GR 159897 (pK<sub>d</sub> 7.8–9.5) [147, 556, 1999], MEN10627 (pK<sub>i</sub> 9.2) [699], nepadutant (pK<sub>i</sub> 8.5–8.7) [314, 394]</td><td>osanetant (pK<sub>i</sub> 8.4–9.7) [57, 125, 393, 555, 1034, 1641, 1868, 1869, 2130], talnetant (pK<sub>i</sub> 7.4–9) [142, 700, 1868, 1869], PD157672 (pIC<sub>50</sub> 7.8–7.9) [182, 2130]</td></tr><tr><td>Labelled ligands</td><td>[<sup>125</sup>I]L703,606 (Antagonist) (pK<sub>d</sub> 9.5) [621], [<sup>125</sup>I]BH-[Sar<sup>9</sup>,Met(O<sub>2</sub>)<sup>11</sup>]<sup>SP</sup> (Agonist) [2150] – Rat, [<sup>3</sup>H]<sup>SP</sup> (human, mouse, rat) (Agonist) [93], [<sup>125</sup>I]<sup>SP</sup> (human, mouse, rat) (Agonist), [<sup>18</sup>F]<sup>SPA-RQ</sup> (Antagonist) [367]</td><td>[<sup>3</sup>H]<sup>saredutant</sup> (Antagonist) (pK<sub>d</sub> 9.7) [749] – Rat, [<sup>125</sup>I]<sup>NKA</sup> (human, mouse, rat) (Agonist) [2267], [<sup>3</sup>H]<sup>GR100679</sup> (Antagonist) (pK<sub>d</sub> 9.2) [778]</td><td>[<sup>3</sup>H]<sup>osanetant</sup> (Antagonist) (pK<sub>d</sub> 9.9), [<sup>3</sup>H]<sup>senktide</sup> (Agonist) [760] – Guinea pig, [<sup>125</sup>I]<sup>[MePhe<sup>7</sup>]<sup>NKB</sup></sup> (Agonist)</td></tr></table>

**Comments:** The NK<sub>1</sub> receptor has also been described to couple to G proteins other than G<sub>q/11</sub> [1828]. The crystal structure of the human NK<sub>1</sub> receptor in complex with antagonists has been determined [1909, 2391]. The hexapeptide agonist sep-

tide appears to bind to an overlapping but non-identical site to substance P (TAC1, P20366) on the NK<sub>1</sub> receptor. There are additional subtypes of tachykinin receptor; an orphan receptor (SwissProt P30098) with structural similarities to the NK<sub>3</sub> receptor was

found to respond to NKB when expressed in *Xenopus* oocytes or Chinese hamster ovary cells [509, 1150].
Further reading on Tachykinin receptors

Douglas SD et al. (2011) Neurokinin-1 receptor: functional significance in the immune system in reference to selected infections and inflammation. *Ann. N. Y. Acad. Sci.* **1217**: 83-95 [PMID:21091716]

Foord SM et al. (2005) International Union of Pharmacology. XLVI. G protein-coupled receptor list. *Pharmacol Rev* **57**: 279-288 [PMID:15914470]

Jones S et al. (2008) The neurokinin 1 receptor: a potential new target for anti-platelet therapy? *Curr Opin Pharmacol* **8**: 114-9 [PMID:18296119]

Steinhoff MS et al. (2014) Tachykinins and their receptors: contributions to physiological control and the mechanisms of disease. *Physiol. Rev.* **94**: 265-301 [PMID:24382888]

Yin J et al. (2018) Crystal structure of the human NK_1 tachykinin receptor. *Proc. Natl. Acad. Sci. U.S.A.* **115**: 13264-13269 [PMID:30538204]

Thyrotropin-releasing hormone receptors

G protein-coupled receptors → Thyrotropin-releasing hormone receptors

**Overview:** Thyrotropin-releasing hormone (TRH) receptors (**provisional nomenclature as recommended by NC-IUPHAR [612]**)) are activated by the endogenous tripeptide TRH (*TRH*, P20396) (pGlu-His-ProNH2). TRH (*TRH*, P20396) and TRH analogues fail to distinguish TRH₁ and TRH₂ receptors [2059]. [³H]TRH (human, mouse, rat) is able to label both TRH₁ and TRH₂ receptors with K<sub>d</sub> values of 13 and 9 nM respectively. Synthesis and biology of ring-modified L-Histidine containing TRH analogues has been reported [1429].

<table><tr><td>Nomenclature</td><td>TRH<sub>1</sub> receptor</td><td>TRH<sub>2</sub> receptor</td></tr><tr><td>HGNC, UniProt</td><td>TRHR, P34981</td><td>–</td></tr><tr><td>Antagonists</td><td>diazepam (pK<sub>i</sub> 5.2) [522] – Rat</td><td>–</td></tr><tr><td>Selective antagonists</td><td>midazolam (pK<sub>i</sub> 5.5) [522] – Rat, chlordiazepoxide (pK<sub>i</sub> 4.8) [522] – Rat, chlordiazepoxide (pK<sub>i</sub> 4.7) [2042] – Mouse</td><td>–</td></tr><tr><td>Comments</td><td>–</td><td>A class A G protein-coupled receptor: not present in man</td></tr></table>

Further reading on Thyrotropin-releasing hormone receptors

Bílek R et al. (2011) TRH-like peptides. *Physiol Res* **60**: 207-15 [PMID:21114375]

Foord SM et al. (2005) International Union of Pharmacology. XLVI. G protein-coupled receptor list. *Pharmacol Rev* **57**: 279-288 [PMID:15914470]

Nillni EA. (2010) Regulation of the hypothalamic thyrotropin releasing hormone (TRH) neuron by neuronal and peripheral inputs. *Front Neuroendocrinol* **31**: 134-56 [PMID:20074584]
# Trace amine receptor

G protein-coupled receptors → Trace amine receptor

**Overview:** Trace amine-associated receptors were discovered from a search for novel 5-HT receptors [205], where 15 mammalian orthologues were identified and divided into two families. The TA₁ receptor **(nomenclature as agreed by the NC-IUPHAR Subcommittee for the Trace amine receptor**

[1355]) has affinity for the endogenous trace amines *tyramine*, *β-phenylethylamine* and *octopamine* in addition to the classical amine dopamine [205]. Emerging evidence suggests that TA₁ is a modulator of monoaminergic activity in the brain [2351] with TA₁ and dopamine D₂ receptors shown to form constitu-

tive heterodimers when co-expressed [572]. In addition to trace amines, receptors can be activated by amphetamine-like psychos- timulants, and endogenous thyronamines.

<table><tr><td>Nomenclature</td><td>TA₁ receptor</td></tr><tr><td>HGNC, UniProt</td><td>TAAR1, Q96RJ0</td></tr><tr><td>Potency order of endogenous ligands</td><td>tyramine > β-phenylethylamine > octopamine = dopamine [205]</td></tr><tr><td>Agonists</td><td>RO5166017 [1790]</td></tr><tr><td>Antagonists</td><td>EPPTB (Inverse agonist) (pIC₅₀ 5.1) [222]</td></tr><tr><td>Labelled ligands</td><td>[³H]tyramine (Agonist) [205]</td></tr></table>

**Comments:** In addition to TA₁, in man there are up to 5 func- tional TAAR genes (TAAR2,5,6,8,9). See [205] for detailed discus- sion. The product of the gene TAAR2 (also known as GPR58) ap- pears to respond to *β-phenylethylamine* > *tyramine* and to couple through Gs [205].

TAAR3, in some individuals, and TAAR4 are pseudogenes in man although functional in rodents. The signalling characteristics and pharmacology of TAAR5 (PNR, Putative Neurotransmitter Re- ceptor: TAAR5, O14804), TAAR6 (Trace amine receptor 4, TaR-4: TAAR6, 96RI8), TAAR8 (Trace amine receptor 5, GPR102: TAAR8, Q969N4 ) and TAAR9 (trace amine associated receptor 9: TAAR9,

96RI9) are lacking. The thyronamines, endogenous derivatives of thyroid hormone, have affinity for rodent cloned trace amine re- ceptors, including TA₁ [1881]. An antagonist EPPTB has recently been described with a pKᵢ of 9.1 at the mouse TA₁ but >5.3 for human TA₁ [2025].

## Further reading on Trace amine receptor

Maguire JJ *et al.* (2009) International Union of Pharmacology. LXXII. Recommendations for trace amine receptor nomenclature. *Pharmacol. Rev.* **61**: 1-8 [PMID:19325074]

Pei Y *et al.* (2016) Trace Amines and the Trace Amine-Associated Receptor 1: Pharmacology, Neuro-chemistry, and Clinical Implications. *Front Neurosci* **10**: 148 [PMID:27092049]
# Urotensin receptor

G protein-coupled receptors → Urotensin receptor

**Overview:** The urotensin-II (U-II) receptor (UT, **nomenclature as agreed by the NC-IUPHAR Subcommittee on the Urotensin receptor [516, 612, 2211]**)) is activated by the endogenous dodecapeptide urotensin-II (UTS2, O95399), originally isolated from the urophysis, the endocrine organ of the caudal neurosecretory system of teleost fish [150, 2210]. Several structural forms of U-II exist in fish and amphibians. The goby orthologue was used to identify U-II as the cognate ligand for the pre-

dicted receptor encoded by the rat gene *gpr14* [425, 1304, 1498, 1603]. Human urotensin-II (UTS2, O95399), an 11-amino-acid peptide [425], retains the cyclohexapeptide sequence of goby U-II that is thought to be important in ligand binding [240, 1101]. This sequence is also conserved in the deduced amino-acid sequence of rat urotensin-II (Rat) (14 amino-acids) and mouse urotensin-II (Mouse) (14 amino-acids), although the N-terminal is more divergent from the human sequence [424]. A second endogenous

ligand for the UT has been discovered in rat [2053]. This is the urotensin II-related peptide (UTS2B, Q765I0), an octapeptide that is derived from a different gene, but shares the C-terminal sequence (CFWKYCV) common to U-II from other species. Identical sequences to rat urotensin II-related peptide (UTS2B, Q765I0) are predicted for the mature mouse and human peptides [523]. UT exhibits relatively high sequence identity with somatostatin, opioid and galanin receptors [2211].

<table><tr><td>Nomenclature</td><td>UT receptor</td></tr><tr><td>HGNC, UniProt</td><td>UTS2R, Q9UKP6</td></tr><tr><td>Endogenous agonists</td><td>urotensin II-related peptide (UTS2B, Q765I0) [523, 1354], urotensin-II (UTS2, O95399) [517, 554, 747]</td></tr><tr><td>Selective agonists</td><td>[Pen<sup>5</sup>]U-(4-11) (human) [747], U-II-(4-11) (human) [747], [3-iodo-Tyr<sup>6</sup>]U-II-(4-11) (human) [1187], Urolinin [104], FL104 [1246, 1248], AC-7954 [436, 1247]</td></tr><tr><td>Selective antagonists</td><td>urantide (pK<sub>i</sub> 8.3) [1661], [Orn<sup>5</sup>]URP (pK<sub>i</sub> 7.2) [492] – Rat, palosuran (pIC<sub>50</sub> 7.1) [402], SB-611812 (pK<sub>i</sub> 6.6) [1760], [Cha<sup>6</sup>]U-II-(4-11) (pK<sub>i</sub> 6.4) [344] – Rat</td></tr><tr><td>Labelled ligands</td><td>[<sup>125</sup>I]U-II (human) (Agonist) [46, 214, 344, 1354], [<sup>125</sup>I]N-biotin-[Ahx<sup>0</sup>, Bpa<sup>3</sup>]U-II (human) [503]</td></tr></table>

**Comments:** In the human vasculature, human urotensin-II (UTS2, O95399) elicits both vasoconstrictor (pD<sub>2</sub> 9.3-10.1, [1354]) and vasodilator (pIC<sub>50</sub> 10.3-10.4, [2035]) responses.

## Further reading on Urotensin receptor

Foord SM *et al.* (2005) International Union of Pharmacology. XLVI. G protein-coupled receptor list. *Pharmacol Rev* **57**: 279-288 [PMID:15914470]

Hunt BD *et al.* (2010) A rat brain atlas of urotensin-II receptor expression and a review of central urotensin-II effects. *Naunyn Schmiedebergs Arch. Pharmacol.* **382**: 1-31 [PMID:20422157]

Maryanoff BE *et al.* (2010) Urotensin-II receptor modulators as potential drugs. *J. Med. Chem.* **53**: 2695-708 [PMID:20043680]

Ross B *et al.* (2010) Role of urotensin II in health and disease. *Am. J. Physiol. Regul. Integr. Comp. Physiol.* **298**: R1156-72 [PMID:20421634]

Vaudry H *et al.* (2015) International Union of Basic and Clinical Pharmacology. XCII. Urotensin II, urotensin II-related peptide, and their receptor: from structure to function. *Pharmacol. Rev.* **67**: 214-58 [PMID:25535277]
# Vasopressin and oxytocin receptors

G protein-coupled receptors → Vasopressin and oxytocin receptors

**Overview:** Vasopressin (AVP) and oxytocin (OT) receptors (nomenclature as recommended by **NC-IUPHAR** [612]) are activated by the endogenous cyclic nonapeptides vasopressin (AVP, P01185) and oxytocin (OXT, P01178). These peptides are derived from precursors which also produce neurophysins (neurophysin I for oxytocin; neurophysin II for vasopressin). Vasopressin and oxytocin differ at only 2 amino acids (positions 3 and 8). There are metabolites of these neuropeptides that may be biologically active [474].

<table><tr><td>Nomenclature</td><td>V<sub>1A</sub> receptor</td><td>V<sub>1B</sub> receptor</td></tr><tr><td>HGNC, UniProt</td><td>AVPR1A, P37288</td><td>AVPR1B, P47901</td></tr><tr><td>Potency order of endogenous ligands</td><td>vasopressin (AVP, P01185) &gt; oxytocin (OXT, P01178) [26, 359, 419, 1541, 1851, 2078, 2115]</td><td>vasopressin (AVP, P01185) &gt; oxytocin (OXT, P01178) [26, 359, 486, 748, 1541, 1851, 2078, 2116]</td></tr><tr><td>Selective agonists</td><td>F180 [53, 419]</td><td>d[Leu<sup>4</sup>]LVP [1679], d[Cha<sup>4</sup>]AVP [486, 748]</td></tr><tr><td>Antagonists</td><td>conivaptan (pK<sub>i</sub> 8.2–8.4) [2078, 2079]</td><td>nelivaptan (pK<sub>i</sub> 8.4–9.3) [748, 1929]</td></tr><tr><td>Selective antagonists</td><td>relcovaptan (pK<sub>i</sub> 8.1–9.3) [26, 419, 748, 2078, 2115], d(CH<sub>2</sub>)<sub>5</sub>[Tyr(Me)<sup>2</sup>,Arg<sup>8</sup>]VP (pK<sub>i</sub> 9)</td><td>–</td></tr><tr><td>Labelled ligands</td><td>[<sup>125</sup>I]OH-LVA (Antagonist) (pK<sub>d</sub> 10.3–10.4) [369, 419], [<sup>3</sup>H]AVP (human, mouse, rat) (Agonist) [231, 369, 2078, 2079, 2115], [<sup>3</sup>H]d(CH<sub>2</sub>)<sub>5</sub>[Tyr(Me)<sup>2</sup>]AVP (Antagonist) (pK<sub>d</sub> 9)</td><td>[<sup>3</sup>H]AVP (human, mouse, rat) (Agonist) [486, 1851, 2078, 2079, 2116]</td></tr></table>

<table><tr><td>Nomenclature</td><td>V<sub>2</sub> receptor</td><td>OT receptor</td></tr><tr><td>HGNC, UniProt</td><td>AVPR2, P30518</td><td>OXTR, P30559</td></tr><tr><td>Potency order of endogenous ligands</td><td>vasopressin (AVP, P01185) &gt; oxytocin (OXT, P01178) [26, 359, 369, 1679, 1927, 2078, 2365]</td><td>oxytocin (OXT, P01178) &gt; vasopressin (AVP, P01185) [26, 369, 370, 396, 748, 984, 1096]</td></tr><tr><td>Selective agonists</td><td>VNA932 [582], OPC-51803 [1541], d[Val<sup>4</sup>,DArg<sup>8</sup>]VP</td><td>[Thr<sup>4</sup>,Gly<sup>7</sup>]OT [370, 551, 984]</td></tr><tr><td>Antagonists</td><td>–</td><td>L-371,257 (pK<sub>i</sub> 8.8) [748]</td></tr><tr><td>Selective antagonists</td><td>conivaptan (pK<sub>i</sub> 9.4) [435], tolvaptan (pK<sub>i</sub> 9.4) [2365], satavaptan (pK<sub>i</sub> 8.4–9.3) [26, 420, 1926, 1927, 2078], lixivaptan (Inverse agonist) (pK<sub>i</sub> 8.9–9.2) [36, 1927], d(CH<sub>2</sub>)<sub>5</sub>[D-Ile<sup>2</sup>,Ile<sup>4</sup>]AVP (pK<sub>i</sub> 6.9–8.4) [420, 1927], mozavaptan (Inverse agonist) (pK<sub>i</sub> 7.4–8.1) [420, 1927, 2078, 2116, 2365]</td><td>SSR126768A (pK<sub>i</sub> 8.8–9.1) [1928], desGlyNH<sub>2</sub>-d(CH<sub>2</sub>)<sub>5</sub>[Tyr(Me)<sup>2</sup>,Thr<sup>4</sup>,Orn<sup>8</sup>]OT (pK<sub>i</sub> 8.5), L-372662 (pK<sub>i</sub> 8.4) [136]</td></tr><tr><td>Labelled ligands</td><td>[<sup>3</sup>H]AVP (human, mouse, rat) (Agonist) [420, 1541, 2078, 2079, 2365], [<sup>3</sup>H]dDAVP (Agonist) [1383], [<sup>3</sup>H]desGly-NH<sub>2</sub>[D-Ile<sup>2</sup>,Ile<sup>4</sup>]VP (pK<sub>d</sub> 8.6)</td><td>[<sup>125</sup>I]d(CH<sub>2</sub>)<sub>5</sub>[Tyr(Me)<sup>2</sup>,Thr<sup>4</sup>,Orn<sup>8</sup>,Tyr-NH<sub>2</sub><sup>9</sup>]OVT (Antagonist) (pK<sub>d</sub> 10), [<sup>3</sup>H]OT (human, mouse, rat) (Agonist) [369, 637, 984, 1098], [<sup>111</sup>In]DOTA-dLVT (pK<sub>d</sub> 8.3) [368]</td></tr></table>
**Comments:** Vasopressin and oxytocin receptors have a char-
acteristic and sometimes overlapping distribution in a num-
ber of tissues including brain. There are phylogenetic, onto-
genetic and sex-specific differences in the levels and distribu-
tion of these receptors, particularly in the brain. The V₂ recep-
tor exhibits marked species differences, such that many ligands

(d(CH₂)₅[D-Ile²,Ile⁴]AVP and [³H]desGly-NH₂[D-Ile²,Ile⁴]VP) ex-
hibit low affinity at human V₂ receptors [31]. Similarly, DAVP
is more V₂ selective in the rat than in the human [1851]. The
gene encoding the V₂ receptor is polymorphic in man, underly-
ing nephrogenic diabetes insipidus [164]. D[Cha⁴]AVP is selec-
tive only for the human and bovine V₁B receptors [486], while

d[Leu⁴]LVP has high affinity for the rat V₁B receptor [1679]. Knockouts of vasopressin and oxytocin receptors have system-specific defects (e.g., impaired ability to concentrate urine in V₂ receptor knockouts) which include behavioural deficits (principally in V₁A, V₁B and OT receptor knockouts).

**Further reading on Vasopressin and oxytocin receptors**

Knepper MA. (2012) Systems biology in physiology: the vasopressin signaling network in kidney. *Am. J. Physiol., Cell Physiol.* **303**: C1115-24 [PMID:22932685]

Koshimizu TA et al. (2012) Vasopressin V1a and V1b receptors: from molecules to physiological systems. *Physiol. Rev.* **92**: 1813-64 [PMID:23073632]

Manning M et al. (2012) Oxytocin and vasopressin agonists and antagonists as research tools and potential therapeutics. *J. Neuroendocrinol.* **24**: 609-28 [PMID:22375852]

Meyer-Lindenberg A et al. (2011) Oxytocin and vasopressin in the human brain: social neuropeptides for translational medicine. *Nat. Rev. Neurosci.* **12**: 524-38 [PMID:21852800]

Neumann ID et al. (2012) Balance of brain oxytocin and vasopressin: implications for anxiety, depression, and social behaviors. *Trends Neurosci.* **35**: 649-59 [PMID:22974560]

VIP and PACAP receptors

G protein-coupled receptors → VIP and PACAP receptors

**Overview:** Vasoactive intestinal peptide (VIP) and pituitary adenylate cyclase-activating peptide (PACAP) receptors (**nomenclature as agreed by the NC-IUPHAR Subcommittee on Vasoactive Intestinal Peptide Receptors [812, 813]**)) are activated by the endogenous peptides VIP (VIP, P01282), PACAP-38 (ADCYAP1, P18509), PACAP-27 (ADCYAP1, P18509), peptide histidine isoleucineamide (PHI (Mouse, Rat)), peptide histidine methionineamide (PHM (VIP, P01282)) and peptide histidine valine (PHV (VIP, P01282)). VPAC₁ and VPAC₂ receptors dis-

play comparable affinity for the PACAP peptides, **PACAP-27** (**ADCYAP1**, P18509) and **PACAP-38** (**ADCYAP1**, P18509), and **VIP** (VIP, P01282), whereas **PACAP-27** (**ADCYAP1**, P18509) and **PACAP-38** (**ADCYAP1**, P18509) are >100 fold more potent than **VIP** (VIP, P01282) as agonists of most isoforms of the **PAC1** receptor. However, one splice variant of the human **PAC1** receptor has been reported to respond to **PACAP-38** (**ADCYAP1**, P18509), **PACAP-27** (**ADCYAP1**, P18509) and **VIP** (VIP, P01282) with comparable affinity [452]. PG 99-465 [1492] has been used as a selec-

tive VPAC₂ receptor antagonist in a number of physiological stud-
ies, but has been reported to have significant activity at VPAC₁
and PAC₁ receptors [493]. The selective PAC₁ receptor agonist
maxadilan, was extracted from the salivary glands of sand flies
(Lutzomyia longipalpis) and has no sequence homology to VIP (VIP,
P01282) or the PACAP peptides [1503]. Two deletion variants of
maxadilan, M65 [2165] and Max.d.4 [1504] have been reported to
be PAC₁ receptor antagonists, but these peptides have not been
extensively characterised.
<table><tr><td>Nomenclature</td><td>PAC<sub>1</sub> receptor</td><td>VPAC<sub>1</sub> receptor</td><td>VPAC<sub>2</sub> receptor</td></tr><tr><td>HGNC, UniProt</td><td>ADCYAP1R1, P41586</td><td>VIPR1, P32241</td><td>VIPR2, P41587</td></tr><tr><td>Potency order of endogenous ligands</td><td>PACAP-27 (ADCYAP1, P18509), PACAP-38 (ADCYAP1, P18509) &gt;&gt; VIP (VIP, P01282)</td><td>VIP (VIP, P01282), PACAP-27 (ADCYAP1, P18509), PACAP-38 (ADCYAP1, P18509) &gt;&gt; GHRH (GHRH, P01286), PHI (Pig), secretin (SCT, P09683)</td><td>VIP (VIP, P01282), PACAP-38 (ADCYAP1, P18509), PACAP-27 (ADCYAP1, P18509) &gt; PHI (Pig) &gt;&gt; GHRH (GHRH, P01286), secretin (SCT, P09683)</td></tr><tr><td>Selective agonists</td><td>maxadilan [493], maxadilan [493]</td><td>[Lys<sup>15</sup>,Arg<sup>16</sup>,Leu<sup>27</sup>]VIP-(1-7)/GRF-(8-27)-NH<sub>2</sub> [1487], [Ala<sup>11,22,28</sup>]VIP [1582]</td><td>Ro 25-1553 [735, 1023, 1487], Ro 25-1392 [2344]</td></tr><tr><td>Selective antagonists</td><td>–</td><td>PG 97-269 (pIC<sub>50</sub> 8.7) [734, 1023]</td><td>–</td></tr><tr><td>Labelled ligands</td><td>[<sup>125</sup>I]PACAP-27 (Agonist) [1712]</td><td>[<sup>125</sup>I]VIP (human, mouse, rat) (Agonist) [1582], [<sup>125</sup>I]PACAP-27 (Agonist)</td><td>[<sup>125</sup>I]VIP (human, mouse, rat) (Agonist) [1582], [<sup>125</sup>I]PACAP-27 (Agonist)</td></tr></table>

**Comments:** Subtypes of PAC<sub>1</sub> receptors have been proposed based on tissue differences in the potencies of PACAP-27 (ADCYAP1, P18509) and PACAP-38 (ADCYAP1, P18509); these might result from differences in G protein coupling and second messenger mechanisms [2195], or from alternative splicing of PAC<sub>1</sub> receptor mRNA [2020].

**Further reading on VIP and PACAP receptors**

Harmar AJ et al. (1998) International Union of Pharmacology. XVIII. Nomenclature of receptors for vasoactive intestinal peptide and pituitary adenylate cyclase-activating polypeptide. *Pharmacol Rev* **50**: 265-270 [PMID:9647867]

Harmar AJ et al. (2012) Pharmacology and functions of receptors for vasoactive intestinal peptide and pituitary adenylate cyclase-activating polypeptide: IUPHAR review 1. *Br. J. Pharmacol.* **166**: 4-17 [PMID:22289055]

Reglodi D et al. (2012) Effects of pituitary adenylate cyclase activating polypeptide in the urinary system, with special emphasis on its protective effects in the kidney. *Neuropeptides* **46**: 61-70 [PMID:21621841]

Smith CB et al. (2012) Is PACAP the major neurotransmitter for stress transduction at the adrenomedullary synapse? *J. Mol. Neurosci.* **48**: 403-12 [PMID:22610912]
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