# Tachykinin receptor 1

The tachykinin receptor 1 (TACR1) also known as neurokinin 1 receptor (NK1R) or substance P receptor (SPR) is a G protein coupled receptor found in the central nervous system and peripheral nervous system. The endogenous ligand for this receptor is Substance P, although it has some affinity for other tachykinins. The protein is the product of the TACR1 gene.

## Structure

Tachykinins are a family of neuropeptides that share the same hydrophobic C-terminal region with the amino acid sequence Phe-X-Gly-Leu-Met-NH$_2$, where X represents a hydrophobic residue that is either an aromatic or a beta-branched aliphatic. The N-terminal region varies between different tachykinins. The term tachykinin originates in the rapid onset of action caused by the peptides in smooth muscles.
Substance P (SP) is the most researched and potent member of the tachykinin family. It is an undecapeptide with the amino acid sequence Arg-Pro-Lys-Pro-Gln-Gln-Phe-Phe-Gly-Leu-Met-NH$_2$. SP binds to all three of the tachykinin receptors, but it binds most strongly to the NK$_1$ receptor.
The tachykinin NK$_1$ receptor consists of 407 amino acid residues, and it has a molecular weight of 58,000. NK$_1$ receptor, as well as the other tachykinin receptors, is made of seven hydrophobic transmembrane (TM) domains with three extracellular and three intracellular loops, an amino-terminus and a cytoplasmic carboxy-terminus. The loops have functional sites, including two cysteines for a disulfide bridge, Asp-Arg-Tyr, responsible for association with arrestin, and Lys/Arg-Lys/Arg-X-X-Lys/Arg, which interacts with G-proteins. The binding site for substance P and other agonists and antagonists is found between the second and third transmembrane domains. The NK-1 receptor is found on human chromosome 2 and is located on the cell's surface as a cytoplasmic receptor.

## Function

The binding of SP to the NK$_1$ receptor has been associated with the transmission of stress signals and pain, the contraction of smooth muscles, and inflammation. NK$_1$ receptor antagonists have also been studied in migraine, emesis, and psychiatric disorders. In fact, aprepitant has been proved effective in a number of pathophysiological models of anxiety and depression. Other diseases in which the NK$_1$ receptor system is involved include asthma, rheumatoid arthritis, and gastrointestinal disorders.

## Tissue distribution

The NK$_1$ receptor can be found in both the central and peripheral nervous system. It is present in neurons, brainstem, vascular endothelial cells, muscle, gastrointestinal tracts, genitourinary tract, pulmonary tissue, thyroid gland, and different types of immune cells.

## Mechanisms of action

SP is synthesized by neurons and transported to synaptic vesicles; the release of SP is accomplished through the depolarizing action of calcium-dependent mechanisms. When NK$_1$ receptors are stimulated, they can generate various second messengers, which can trigger a wide range of effector mechanisms that regulate cellular excitability and function.
There are three well-defined, independent second messenger systems:
* Stimulation via phospholipase C, leading to phosphatidyl inositol turnover and Ca mobilization from both intra- and extracellular sources.
* Arachidonic acid mobilization via phospholipase A2.
* cAMP accumulation via stimulation of adenylate cyclase.
It has also been reported that SP elicits interleukin-1 (IL-1) production in macrophages, sensitizes neutrophils, and enhances dopamine release in the substantia nigra region in cat brain. From spinal neurons, SP is known to evoke release of neurotransmitters like acetylcholine, histamine, and GABA. It also secretes catecholamines and plays a role in the regulation of blood pressure and hypertension. Likewise, SP is known to bind to N-methyl-D-aspartate (NMDA) receptors, eliciting excitation with calcium ion influx, which further releases nitric oxide. Studies in frogs have shown that SP elicits the release of prostaglandin E$_2$ and prostacyclin by the arachidonic acid pathway, which leads to an increase in corticosteroid output.

## Clinical significance

In combination therapy, NK$_1$ receptor antagonists appear to offer better control of delayed emesis and post-operative emesis than drug therapy without NK$_1$ receptor antagonists. NK$_1$ receptor antagonists block responses to a broader range of emetic stimuli than the established 5-HT$_3$ antagonist treatments. It has been reported that centrally-acting NK$_1$ receptor antagonists, such as CP-99994, inhibit emesis induced by apomorphine and loperimidine, which are two compounds that act through central mechanisms.
This receptor is considered an attractive drug target, particularly with regards to potential analgesics and anti-depressants. It is also a potential treatment for alcoholism and opioid addiction. In addition, it has been identified as a candidate in the etiology of bipolar disorder. Finally NK1R antagonists may also have a role as novel antiemetics and hypnotics.
Neurokinin receptor 1 (NK-1R) also plays a significant role in cancer progression. NK-1R is overexpressed in various cancer types and is activated by substance P (SP). This activation promotes tumor cell proliferation, migration, and invasion while inhibiting apoptosis. The SP/NK-1R system is involved in angiogenesis, chronic inflammation, and the Warburg effect, all of which contribute to tumor growth. NK-1R antagonists, such as aprepitant, have shown promise as potential anticancer treatments by inhibiting tumor growth, inducing apoptosis, and blocking metastasis. The overexpression of NK-1R in tumors may also serve as a prognostic biomarker.

## Ligands

Many selective ligands for NK$_1$ are now available, several of which have gone into clinical use as antiemetics.

### Agonists

* GR-73632 - potent and selective agonist, EC$_{50}$ 2nM, 5-amino acid polypeptide chain. CAS# 133156-06-6

### Antagonists

* Aprepitant
* Casopitant
* Elinzanetant
* Ezlopitant
* Fosaprepitant
* Lanepitant
* Maropitant
* Rolapitant
* Vestipitant
* L-733,060
* L-741,671
* L-742,694
* RP-67580 - potent and selective antagonist, Ki 2.9nM, (3aR,7aR)-Octahydro-2-[1-imino-2-(2-methoxyphenyl)ethyl ]-7,7-diphenyl-4H-isoindol, CAS# 135911-02-3
* RPR-100,893
* CP-96345
* CP-99994
* GR-205,171/Vofopitant
* TAK-637
* T-2328