Target Information

Target General Infomation
Target ID
T29683
Former ID
TTDC00117
Target Name
Nigral tachykinin NK(3) receptor
Gene Name
TACR3
Synonyms
NK-3 receptor; NK-3R; NKR; Neurokinin B receptor; Neurokinin-3 receptor; Neuromedin K receptor; Tachykinin receptor 3; TACR3
Target Type
Clinical Trial
Disease Asthma [ICD10: J45]
Chronic obstructive pulmonary disease [ICD9: 490-492, 494-496; ICD10: J40-J44, J47]
Central nervous system disease [ICD10: G00-G99]
Depression [ICD9: 311; ICD10: F30-F39]
Irritable bowel syndrome [ICD9: 564.1, 787.91; ICD10: A09, K58, K59.1]
Psychiatric disorder [ICD9: 290-319; ICD10: F01-F99]
Psychotic disorders [ICD9: 290-299; ICD10: F20-F29]
Schizophrenia [ICD9: 295; ICD10: F20]
Schizophrenia; Schizoaffective disorders [ICD9: 295, 295.70; ICD10: F20, F25]
Function
This is a receptor for the tachykinin neuropeptide neuromedin-K (neurokinin B). It is associated with G proteins that activate a phosphatidylinositol-calcium second messenger system. The rank order of affinity of this receptor to tachykinins is: neuromedin-K > substance K > substance P.
BioChemical Class
GPCR rhodopsin
Target Validation
T29683
UniProt ID
P29371
Sequence
MATLPAAETWIDGGGGVGADAVNLTASLAAGAATGAVETGWLQLLDQAGNLSSSPSALGL
PVASPAPSQPWANLTNQFVQPSWRIALWSLAYGVVVAVAVLGNLIVIWIILAHKRMRTVT
NYFLVNLAFSDASMAAFNTLVNFIYALHSEWYFGANYCRFQNFFPITAVFASIYSMTAIA
VDRYMAIIDPLKPRLSATATKIVIGSIWILAFLLAFPQCLYSKTKVMPGRTLCFVQWPEG
PKQHFTYHIIVIILVYCFPLLIMGITYTIVGITLWGGEIPGDTCDKYHEQLKAKRKVVKM
MIIVVMTFAICWLPYHIYFILTAIYQQLNRWKYIQQVYLASFWLAMSSTMYNPIIYCCLN
KRFRAGFKRAFRWCPFIKVSSYDELELKTTRFHPNRQSSMYTVTRMESMTVVFDPNDADT
TRSSRKKRATPRDPSFNGCSRRNSKSASATSSFISSPYTSVDEYS
Drugs and Mode of Action
Drug(s) SB222200 Drug Info Preclinical Schizophrenia; Schizoaffective disorders [1], [2]
Osanetant Drug Info Discontinued in Phase 2b Schizophrenia; Schizoaffective disorders [3], [4]
AZD2624 Drug Info Discontinued in Phase 2 Schizophrenia [5], [6]
CS-003 Drug Info Discontinued in Phase 2 Chronic obstructive pulmonary disease [7]
Talnetant Drug Info Discontinued in Phase 2 Irritable bowel syndrome [8], [9]
Talnetant Drug Info Discontinued in Phase 2 Schizophrenia; Schizoaffective disorders [8], [9]
GSK1144814 Drug Info Discontinued in Phase 1 Schizophrenia [10]
SSR-146977 Drug Info Discontinued in Phase 1 Psychotic disorders [11], [12]
Osanetant Drug Info Terminated Depression [3], [4]
Inhibitor 2-phenyl-N-(1-phenylethyl)quinoline-4-carboxamide Drug Info [13]
3-methoxy-N',2-diphenylquinoline-4-carbohydrazide Drug Info [14]
N-phenethyl-2-phenylquinoline-4-carboxamide Drug Info [13]
NEUROKININ B Drug Info [15]
PD-157672 Drug Info [15]
PD-160946 Drug Info [16]
PD-161182 Drug Info [16]
Modulator AZD2624 Drug Info
GSK1144814 Drug Info
Antagonist CS-003 Drug Info [7]
GR138676 Drug Info [17]
GSK-172981 Drug Info [18]
N',2-diphenylquinoline-4-carbohydrazide Drug Info [14]
N',2-diphenylquinoline-4-carbohydrazide 8m Drug Info [19]
NK-3 antagonists Drug Info [18]
NK3 antagonist PET ligand Drug Info [18]
Osanetant Drug Info [20], [21], [22]
PD 154740 Drug Info [23]
R-820 Drug Info [24]
SB222200 Drug Info [25], [26], [27]
SCH 206272 Drug Info [28]
SSR-146977 Drug Info [29]
Talnetant Drug Info [20], [21], [22]
[3H]osanetant Drug Info [18]
Agonist eledoisin Drug Info [30]
kassinin Drug Info [31]
neurokinin A Drug Info [32]
Senktide Drug Info [24], [33]
Target Expression Profile (TEP) and Drug Resistance Mutation (DRM)
TEP EXP Info
Pathways
KEGG Pathway Calcium signaling pathway
Neuroactive ligand-receptor interaction
Reactome G alpha (q) signalling events
WikiPathways Gastrin-CREB signalling pathway via PKC and MAPK
Peptide GPCRs
GPCR ligand binding
GPCR downstream signaling
References
REF 1Nonpeptide tachykinin receptor antagonists. II. Pharmacological and pharmacokinetic profile of SB-222200, a central nervous system penetrant, potent and selective NK-3 receptor antagonist. J Pharmacol Exp Ther. 2000 Oct;295(1):373-81.
REF 2(http://www.guidetopharmacology.org/) Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 2131).
REF 3The pipeline and future of drug development in schizophrenia. Mol Psychiatry. 2007 Oct;12(10):904-22. Epub 2007 Jul 31.
REF 4(http://www.guidetopharmacology.org/) Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 2110).
REF 5ClinicalTrials.gov (NCT00686998) Phase IIA Study in Patients With Schizophrenia. U.S. National Institutes of Health.
REF 6(http://www.guidetopharmacology.org/) Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 5775).
REF 7Emerging drugs for the treatment of chronic obstructive pulmonary disease. Expert Opin Emerg Drugs. 2006 May;11(2):275-91.
REF 8Emerging drugs for irritable bowel syndrome. Expert Opin Emerg Drugs. 2006 May;11(2):293-313.
REF 9(http://www.guidetopharmacology.org/) Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 2132).
REF 10ClinicalTrials.gov (NCT01090440) Pharmacokinetics, Effect of Food, Safety and Tolerability of a New Tablet Formulation of GSK1144814 in Healthy Subjects. U.S. National Institutes of Health.
REF 11(http://www.guidetopharmacology.org/) Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 2133).
REF 12Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800014351)
REF 13J Med Chem. 2010 Nov 25;53(22):8080-8. Epub 2010 Nov 3.Virtual screening to identify novel antagonists for the G protein-coupled NK3 receptor.
REF 14Bioorg Med Chem Lett. 2006 Nov 15;16(22):5748-51. Epub 2006 Sep 6.N',2-diphenylquinoline-4-carbohydrazide based NK3 receptor antagonists.
REF 15The rational development of small molecule tachykinin NK3 receptor selective antagonists - the utilisation of a dipeptide chemical library in drug design, Bioorg. Med. Chem. Lett. 4(14):1679-1684 (1994).
REF 16The development of a novel series of non-peptide tachykinin NK3 receptor selective antagonists, Bioorg. Med. Chem. Lett. 5(16):1773-1778 (1995).
REF 17GR138676, a novel peptidic tachykinin antagonist which is potent at NK3 receptors. Neuropeptides. 1994 Dec;27(6):333-41.
REF 18(http://www.guidetopharmacology.org/) Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Target id: 362).
REF 19N',2-diphenylquinoline-4-carbohydrazide based NK3 receptor antagonists II. Bioorg Med Chem Lett. 2006 Nov 15;16(22):5752-6. Epub 2006 Sep 6.
REF 20Augmentation of antipsychotic-induced neurochemical changes by the NK3 receptor antagonist talnetant (SB-223412). Neuropharmacology. 2009 Feb;56(2):342-9. Epub 2008 Sep 18.
REF 21The tachykinin NK3 receptor agonist senktide induces locomotor activity in male Mongolian gerbils. Eur J Pharmacol. 2008 Dec 14;600(1-3):87-92. Epub 2008 Oct 10.
REF 22Pharmacological characterization of senktide-induced tail whips. Neuropharmacology. 2009 Jun 21.
REF 23Two classes of structurally different antagonists display similar species preference for the human tachykinin neurokinin3 receptor. Mol Pharmacol. 1995 Oct;48(4):711-6.
REF 24Implication of nigral tachykinin NK3 receptors in the maintenance of hypertension in spontaneously hypertensive rats: a pharmacologic and autoradiographic study. Br J Pharmacol. 2003 Feb;138(4):554-63.
REF 25Substance P depolarizes striatal projection neurons and facilitates their glutamatergic inputs. J Physiol. 2008 Apr 15;586(8):2143-55. Epub 2008 Feb 28.
REF 26Neurokinin B/NK3 receptors exert feedback inhibition on L-DOPA actions in the 6-OHDA lesion rat model of Parkinson's disease. Neuropharmacology. 2008 Jun;54(7):1143-52. Epub 2008 Mar 18.
REF 27Evidence for mediation of nociception by injection of the NK-3 receptor agonist, senktide, into the dorsal periaqueductal gray of rats. Psychopharmacology (Berl). 2009 May;204(1):13-24. Epub 2008 Dec 18.
REF 28SCH 206272: a potent, orally active tachykinin NK(1), NK(2), and NK(3) receptor antagonist. Eur J Pharmacol. 2002 Aug 23;450(2):191-202.
REF 29Biochemical and pharmacological activities of SSR 146977, a new potent nonpeptide tachykinin NK3 receptor antagonist. Can J Physiol Pharmacol. 2002 May;80(5):482-8.
REF 30Molecular characterisation, expression and localisation of human neurokinin-3 receptor. FEBS Lett. 1992 Mar 24;299(1):90-5.
REF 31The unpredicted high affinities of a large number of naturally occurring tachykinins for chimeric NK1/NK3 receptors suggest a role for an inhibitory domain in determining receptor specificity. J BiolChem. 1996 Aug 23;271(34):20250-7.
REF 32Molecular and pharmacological characterization of the murine tachykinin NK(3) receptor. Eur J Pharmacol. 2001 Feb 16;413(2-3):143-50.
REF 33Neurokinin-3 receptors modulate dopamine cell function and alter the effects of 6-hydroxydopamine. Brain Res. 1995 Oct 9;695(1):19-24.

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