Overview: Tachykinin receptors (provisional nomenclature, see Foord et al., 2005) are activated by the endogenous peptides substance P (SP), neurokinin A (NKA; previously known as substance K, neurokinin α, neuromedin L), neurokinin B (NKB; previously known as neurokinin β, neuromedin K), neuropeptide K and neuropeptide γ (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 non-mammalian origin containing the consensus sequence: Phe-x-Gly-Leu-Met. Marked species differences in pharmacology exist for all three receptors, in particular with non-peptide ligands.
| Nomenclature | NK1 | NK2 | NK3 |
|---|---|---|---|
| Other names | Substance P | Substance K | Neurokinin B, neuromedin K |
| Ensembl ID | ENSG00000115353 | ENSG00000075073 | ENSG00000169836 |
| Principal transduction | Gq/11 | Gq/11 | Gq/11 |
| Rank order of potency | SP > NKA > NKB | NKA > NKB >> SP | NKB > NKA > SP |
| Selective agonists | SP methylester, [Sar9,Met(O2)11]SP, [Pro9]SP, septide | [β-Ala8]NKA-(4-10),[Lys5,Me-Leu9,Mle10] NKA-(4-10), GR64349 | Senktide, [MePhe7]NKB |
| Selective antagonists | Aprepitant (10.7; Hale et al., 1998), SR140333 (9.5), LY303870 (9.4), CP99994 (9.3), RP67580 (7.6) | GR94800 (9.6), GR159897 (9.5), MEN10627 (9.2), SR48968 (9.0), MEN11420 (8.6; Catalioto et al., 1998) | SR142802 (9.2), SB223412 (9.0; Sarau et al., 1997), PD157672 (7.8) |
| Probes | [3H]- or [125I]-SP, [3H]- or [125I]-BH-[Sar9,Met(O2)11]SP, [125I]-L703606 (0.3 nM), [18F]-SPA-RQ | [3H]-SR48968 (0.5 nM), [3H]-GR100679, [125I]-NKA | [3H]-Senktide, [125I]-[MePhe7]NKB, [3H]-SR142801 (0.13 nM) |
The NK1 receptor has also been described to couple to other G proteins (Roush and Kwatra, 1998). The hexapeptide agonist septide appears to bind to an overlapping but non-identical site to SP on the NK1 receptor. There are suggestions for additional subtypes of tachykinin receptor; an orphan receptor (SwissProt P30098) with structural similarities to the NK3 receptor was found to respond to NKB when expressed in Xenopus oocytes or Chinese hamster ovary cells (Donaldson et al., 1996; Krause et al., 1997).
Glossary
Abbreviations:
- [18F]-SPA-RQ
([[18F]-2-fluoromethoxy-5-(5-trifluoromethyl-tetrazol-1-yl)-benzyl]([2S,3S]2-phenyl-piperidin-3-yl)-amine
- Aprepitant
5-[[(2R,3S]-2-[(1R)-1-[3,5-bis(trifluoromethyl) phenyl]ethoxy]-3-(4-fluorphenyl)-4-morpholinyl]methyl]-1,2-dihydro-3H-1,2,4-triazol-3-one (also known as Emend)
- CP99994
(+)-(2S,3S)-3-(2-methoxybenzylamino)-2-phenylpiperidine
- GR100679
cyclohexylcarbonyl-Gly-Ala-DTrp-Phe-NMe2
- GR159897
(R)-1-(2-[5-fluoro-1H-indol-3-yl]ethyl)-4-methoxy-4([phenylsulfinyl]methyl)piperidine
- GR64349
Lys-Asp-Ser-Phe-Val-Gly-(r-γ-lactam)
- GR94800
N-α-benzoyl-Ala-Ala-DTrp-Phe-DPro-Pro-Nle-NH2
- L-703606
cis-2(diphenylmethyl)-N-([2-iodophenyl]methyl)-1-azabicyclo[2.2.2]octan-3-amide
- L-742694
2(s)-([3,5-bis{trifluoromethyl}benzyl]-oxy)-3(S)-phenyl-4-([3-oxo-1,2,4-triazol-5-yl]methyl)morpholine
- LY303870
(r)-1-(N-[2-methoxybenzyl]acetylamino)-3-(1H-indol-3yl)-2-(N-[2-{4-(piperidin-1-yl)piperidin-1-yl}acetyl]amino)propane; also known as lanepitant
- MEN10627
cyc(2β–5β)(Met-Asp-Trp-Phe-Dap-Leu)
- MEN11420
cyc(2β–5β)[Asn(2-AcNH-β-D-Glc)-Asp-Trp-Phe-Dap-Leu] also known as nepadutant
- PD157672
Boc-(s)Phe-(r)αMePheNH(CH2)7NHCONH2
- RP67580
3αR,7αR-(1-imino-2-[2-methoxyphenyl]ethyl)-7,7-diphenyl-4-perhydroisoindolone
- SB223412
(s)-(-)-N-(α-ethylbenzyl)-3-hydroxy-2-phenylquinoline-4-carboxamide
- SR140333
(s)-1-(2-[3-{3,4-dichlorophenyl}-1-{3-isopropoxyphenylacetyl}piperidin-3-yl]ethyl)-4-phenyl-1-azoniabicyclo(2.2.2)octane chloride
- SR142801
(s)-(N)-(1-[3-{1-benzoyl-3-(3,4-dichlorophenyl)piperidin-3-yl}propyl]-4-phenylpiperidin-4-yl)-N-methylacetamide
- SR48968
(s)-N-methyl-N-(4-acetylamino-4-phenylpiperidino)-2-(3,4-dichlorophenyl)butylbenzamide; also known as saredutant
Further Reading
Brain SD, Cox HM (2006). Neuropeptides and their receptors: innovative science providing novel therapeutic targets. Br J Pharmacol147: S202–S211.
Diemunsch P, Joshi GP, Brichant JF (2009). Neurokinin-1 receptor antagonists in the prevention of postoperative nausea and vomiting. Br J Anaesth103: 7–13.
Foord SM, Bonner TI, Neubig RR, Rosser EM, Pin JP, Davenport AP et al. (2005). International Union of Pharmacology. XLVI. G protein-coupled receptor list. Pharmacol Rev57: 279–288.
Hoogerwerf WA, Sarna SK (2006). Tachykinin receptors as drug targets for motility disorders. Dig Dis24: 83–90.
Jones S, Gibbins JM (2008). The neurokinin 1 receptor: a potential new target for anti-platelet therapy? Curr Opin Pharmacol8: 114–119.
Quartara L, Altamura M (2006). Tachykinin receptors antagonists: from research to clinic. Curr Drug Targets7: 975–992.
References
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