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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.[1]

Clinical significance[edit | edit source]

This receptor is considered an attractive drug target, particularly with regards to potential analgesics and anti-depressants.[2] It was identified as a candidate in the etiology of bipolar disorder by a 2008 study.[3] Furthermore TACR1 antagonists have shown promise for the treatment in alcoholism.[4] Finally TACR1 antagonists may also have a role as novel antiemetics.[5]

Selective ligands[edit | edit source]

Many selective ligands for NK1 are now available, several of which have gone into clinical use as antiemetics.

Agonists[edit | edit source]

  • GR-73632 - potent and selective agonist, EC50 2nM, 5-amino acid polypeptide chain. CAS# 133156-06-6

Antagonists[edit | edit source]

  • Aprepitant
  • Casopitant
  • Fosaprepitant
  • Maropitant
  • Ezlopitant
  • Lanepitant
  • 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
  • TAK-637
  • T-2328

See also[edit | edit source]

References[edit | edit source]

  1. Takeda Y, Chou KB, Takeda J, Sachais BS, Krause JE (1991). Molecular cloning, structural characterization and functional expression of the human substance P receptor. Biochem. Biophys. Res. Commun. 179 (3): 1232–40.
  2. Humphrey JM (2003). Medicinal chemistry of selective neurokinin-1 antagonists. Current topics in medicinal chemistry 3 (12): 1423–35.
  3. Perlis RH, Purcell S, Fagerness J, Kirby A, Petryshen TL, Fan J, Sklar P (January 2008). Family-based association study of lithium-related and other candidate genes in bipolar disorder. Arch. Gen. Psychiatry 65 (1): 53–61.
  4. George DT, Gilman J, Hersh J, Thorsell A, Herion D, Geyer C, Peng X, Kielbasa W, Rawlings R, Brandt JE, Gehlert DR, Tauscher JT, Hunt SP, Hommer D, Heilig M (March 2008). Neurokinin 1 receptor antagonism as a possible therapy for alcoholism. Science (journal) 319 (5869): 1536–9.
  5. Jordan K (2006). Neurokinin-1-receptor antagonists: a new approach in antiemetic therapy. Onkologie 29 (1-2): 39–43.

Further reading[edit | edit source]

  • Burcher E (1989). The study of tachykinin receptors.. Clin. Exp. Pharmacol. Physiol. 16 (6): 539-43.
  • Kowall NW, Quigley BJ, Krause JE, et al. (1993). Substance P and substance P receptor histochemistry in human neurodegenerative diseases.. Regul. Pept. 46 (1-2): 174-85.
  • Patacchini R, Maggi CA (2002). Peripheral tachykinin receptors as targets for new drugs.. Eur. J. Pharmacol. 429 (1-3): 13-21.
  • Saito R, Takano Y, Kamiya HO (2003). Roles of substance P and NK(1) receptor in the brainstem in the development of emesis.. J. Pharmacol. Sci. 91 (2): 87-94.
  • Fong TM, Yu H, Huang RR, Strader CD (1992). The extracellular domain of the neurokinin-1 receptor is required for high-affinity binding of peptides.. Biochemistry 31 (47): 11806-11.
  • Fong TM, Huang RR, Strader CD (1993). Localization of agonist and antagonist binding domains of the human neurokinin-1 receptor.. J. Biol. Chem. 267 (36): 25664-7.
  • Fong TM, Anderson SA, Yu H, et al. (1992). Differential activation of intracellular effector by two isoforms of human neurokinin-1 receptor.. Mol. Pharmacol. 41 (1): 24-30.
  • Takahashi K, Tanaka A, Hara M, Nakanishi S (1992). The primary structure and gene organization of human substance P and neuromedin K receptors.. Eur. J. Biochem. 204 (3): 1025-33.
  • Walsh DA, Mapp PI, Wharton J, et al. (1992). Localisation and characterisation of substance P binding to human synovial tissue in rheumatoid arthritis.. Ann. Rheum. Dis. 51 (3): 313-7.
  • Gerard NP, Garraway LA, Eddy RL, et al. (1991). Human substance P receptor (NK-1): organization of the gene, chromosome localization, and functional expression of cDNA clones.. Biochemistry 30 (44): 10640-6.
  • Hopkins B, Powell SJ, Danks P, et al. (1991). Isolation and characterisation of the human lung NK-1 receptor cDNA.. Biochem. Biophys. Res. Commun. 180 (2): 1110-7.
  • Takeda Y, Chou KB, Takeda J, et al. (1991). Molecular cloning, structural characterization and functional expression of the human substance P receptor.. Biochem. Biophys. Res. Commun. 179 (3): 1232-40.
  • Giuliani S, Barbanti G, Turini D, et al. (1992). NK2 tachykinin receptors and contraction of circular muscle of the human colon: characterization of the NK2 receptor subtype.. Eur. J. Pharmacol. 203 (3): 365-70.
  • Ichinose H, Katoh S, Sueoka T, et al. (1991). Cloning and sequencing of cDNA encoding human sepiapterin reductase--an enzyme involved in tetrahydrobiopterin biosynthesis.. Biochem. Biophys. Res. Commun. 179 (1): 183-9.
  • Thöny B, Heizmann CW, Mattei MG (1995). Human GTP-cyclohydrolase I gene and sepiapterin reductase gene map to region 14q21-q22 and 2p14-p12, respectively, by in situ hybridization.. Genomics 26 (1): 168-70.
  • Fong TM, Cascieri MA, Yu H, et al. (1993). Amino-aromatic interaction between histidine 197 of the neurokinin-1 receptor and CP 96345.. Nature 362 (6418): 350-3.
  • Derocq JM, Ségui M, Blazy C, et al. (1997). Effect of substance P on cytokine production by human astrocytic cells and blood mononuclear cells: characterization of novel tachykinin receptor antagonists.. FEBS Lett. 399 (3): 321-5.
  • De Felipe C, Herrero JF, O'Brien JA, et al. (1998). Altered nociception, analgesia and aggression in mice lacking the receptor for substance P.. Nature 392 (6674): 394-7.

External links[edit | edit source]

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