Target Information

Target General Infomation
Target ID
T52790
Former ID
TTDC00090
Target Name
NK-2 receptor
Gene Name
TACR2
Synonyms
NK-2 receptor; NK-2R; Neurokinin A receptor; SKR; Tachykinin neurokinin 2 receptor; Tachykinin receptor 2; TACR2
Target Type
Clinical Trial
Disease Asthma [ICD10: J45]
Anxiety disorder [ICD9: 300, 311; ICD10: F32, F40-F42]
Chronic obstructive pulmonary disease [ICD9: 490-492, 494-496; ICD10: J40-J44, J47]
Depression; Anxiety [ICD9: 300, 311; ICD10: F30-F39, F40-F42]
Depression; Acute or chronic pain; Anxiety disorders; Urinary incontinence [ICD9: 300, 311, 338, 338.2, 787.6, 788.3,780; ICD10: F30-F42, N39.3-N39.4, G89]
Infantile colics; Postoperative ileus [ICD9: 537.2, 560.1, 560.31, 777.1, 777.4, 789.7; ICD10: K31.5, K56.0, K56.3, K56.7, P76.1, R10.4]
Irritable bowel syndrome [ICD9: 564.1, 787.91; ICD10: A09, K58, K59.1]
Irritable bowel syndrome with diarrhoea [ICD9: 493, 564.1, 787.91; ICD10: A09, J45, K58, K59.1]
Pain [ICD9: 338, 356.0, 356.8,780; ICD10: G64, G90.0, R52, G89]
Urinary incontinence [ICD9: 788.3; ICD10: N39.3, N39.4, R32]
Unspecified [ICD code not available]
Function
This is a receptor for the tachykinin neuropeptide substance K (neurokinin A). 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: substance K > neuromedin-K > substance P.
BioChemical Class
GPCR rhodopsin
Target Validation
T52790
UniProt ID
P21452
Sequence
MGTCDIVTEANISSGPESNTTGITAFSMPSWQLALWATAYLALVLVAVTGNAIVIWIILA
HRRMRTVTNYFIVNLALADLCMAAFNAAFNFVYASHNIWYFGRAFCYFQNLFPITAMFVS
IYSMTAIAADRYMAIVHPFQPRLSAPSTKAVIAGIWLVALALASPQCFYSTVTMDQGATK
CVVAWPEDSGGKTLLLYHLVVIALIYFLPLAVMFVAYSVIGLTLWRRAVPGHQAHGANLR
HLQAMKKFVKTMVLVVLTFAICWLPYHLYFILGSFQEDIYCHKFIQQVYLALFWLAMSST
MYNPIIYCCLNHRFRSGFRLAFRCCPWVTPTKEDKLELTPTTSLSTRVNRCHTKETLFMA
GDTAPSEATSGEAGRPQDGSGLWFGYGLLAPTKTHVEI
Drugs and Mode of Action
Drug(s) Ibodutant Drug Info Phase 3 Irritable bowel syndrome [1], [2]
Nepadutant Drug Info Phase 1/2 Infantile colics; Postoperative ileus [3], [4]
SLV-332 Drug Info Preclinical Irritable bowel syndrome [5]
Saredutant Drug Info Discontinued in Phase 3 Depression; Anxiety [6], [7]
CS-003 Drug Info Discontinued in Phase 2 Chronic obstructive pulmonary disease [8]
DNK-333 Drug Info Discontinued in Phase 2 Irritable bowel syndrome with diarrhoea [8]
FK-224 Drug Info Discontinued in Phase 2 Asthma [9], [10]
AVE-5883 Drug Info Discontinued in Phase 1/2 Asthma [11]
SR 144190 Drug Info Discontinued in Phase 1 Depression; Acute or chronic pain; Anxiety disorders; Urinary incontinence [12]
UK-224671 Drug Info Discontinued in Phase 1 Urinary incontinence [13]
AZD-5106 Drug Info Terminated Urinary incontinence [14]
GR-159897 Drug Info Terminated Anxiety disorder [15], [16]
L-732138 Drug Info Terminated Discovery agent [17]
MEN-10207 Drug Info Terminated Pain [18]
MEN-10627 Drug Info Terminated Asthma [19], [20]
UK-290795 Drug Info Terminated Urinary incontinence [21]
ZD-7944 Drug Info Terminated Asthma [22]
Inhibitor 4-(4-butylpiperidin-1-yl)-1-o-tolylbutan-1-one Drug Info [23]
A-987306 Drug Info [24]
Ac-Phe-[Orn-Pro-cha-Trp-Arg] Drug Info [25]
Hoo-Phe-Orn-Pro-hle-Pff-Phe-NH2 Drug Info [25]
L-732138 Drug Info [26]
WAY-207024 Drug Info [27]
Modulator AVE-5883 Drug Info [28]
DNK-333 Drug Info
FK-224 Drug Info [29]
GR-159897 Drug Info [30]
MEN-10207 Drug Info [31]
MEN-10627 Drug Info [32]
ZD-6021 Drug Info
ZD-7944 Drug Info [33]
Antagonist AZD-5106 Drug Info [34]
CS-003 Drug Info [8]
GR100679 Drug Info [35]
GR94800 Drug Info [36]
Ibodutant Drug Info [37]
MEN13510 Drug Info [38]
Nepadutant Drug Info [3]
R396 Drug Info [39]
Saredutant Drug Info [40], [41], [42]
SCH 206272 Drug Info [43]
SLV-332 Drug Info [5]
SR 144190 Drug Info [44], [45]
UK-224671 Drug Info [46]
UK-290795 Drug Info [47]
YM44778 Drug Info [48]
YM44781 Drug Info [48]
YM49598 Drug Info [48]
ZM 253270 Drug Info [49]
ZM-274773 Drug Info [50]
[3H]saredutant Drug Info [51]
Agonist neurokinin A Drug Info [52]
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 1ClinicalTrials.gov (NCT02320318) 12-Week Efficacy and Safety Study of Ibodutant in Women With Irritable Bowel Syndrome With Diarrhea (IBS-D). U.S. National Institutes of Health.
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: 2117).
REF 3Emerging drugs for postoperative ileus. Expert Opin Emerg Drugs. 2007 Nov;12(4):619-26.
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: 2123).
REF 5Emerging drugs for irritable bowel syndrome. Expert Opin Emerg Drugs. 2006 May;11(2):293-313.
REF 6Novel drugs and therapeutic targets for severe mood disorders. Neuropsychopharmacology. 2008 Aug;33(9):2080-92. Epub 2008 Jan 2.
REF 7(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: 2111).
REF 8Emerging drugs for the treatment of chronic obstructive pulmonary disease. Expert Opin Emerg Drugs. 2006 May;11(2):275-91.
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: 2103).
REF 10Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800001455)
REF 11Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800021516)
REF 12Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800008589)
REF 13Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800010850)
REF 14Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800015341)
REF 15(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: 2115).
REF 16Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800003215)
REF 17Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800006439)
REF 18Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800003687)
REF 19(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: 3901).
REF 20Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800004991)
REF 21Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800017162)
REF 22Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800007349)
REF 23J Med Chem. 2010 Sep 9;53(17):6386-97.Discovery of N-{1-[3-(3-oxo-2,3-dihydrobenzo[1,4]oxazin-4-yl)propyl]piperidin-4-yl}-2-phenylacetamide (Lu AE51090): an allosteric muscarinic M1 receptor agonist with unprecedented selectivity and procognitive potential.
REF 24J Med Chem. 2008 Nov 27;51(22):7094-8.cis-4-(Piperazin-1-yl)-5,6,7a,8,9,10,11,11a-octahydrobenzofuro[2,3-h]quinazolin-2-amine (A-987306), a new histamine H4R antagonist that blocks pain responses against carrageenan-induced hyperalgesia.
REF 25Bioorg Med Chem Lett. 2006 Oct 1;16(19):5088-92. Epub 2006 Jul 28.Peptidomimetic C5a receptor antagonists with hydrophobic substitutions at the C-terminus: increased receptor specificity and in vivoactivity.
REF 26J Med Chem. 2010 Aug 12;53(15):5491-501.Biological and conformational evaluation of bifunctional compounds for opioid receptor agonists and neurokinin 1 receptor antagonists possessing two penicillamines.
REF 27J Med Chem. 2009 Apr 9;52(7):2148-52.Discovery of 6-({4-[2-(4-tert-butylphenyl)-1H-benzimidazol-4-yl]piperazin-1-yl}methyl)quinoxaline (WAY-207024): an orally active antagonist of the gonadotropin releasing hormone receptor (GnRH-R).
REF 28Effect of an NK1/NK2 receptor antagonist on airway responses and inflammation to allergen in asthma. Am J Respir Crit Care Med. 2007 Mar 1;175(5):450-7. Epub 2006 Dec 14.
REF 29FK 224, a novel cyclopeptide substance P antagonist with NK1 and NK2 receptor selectivity. J Pharmacol Exp Ther. 1992 Jul;262(1):398-402.
REF 30GR159897, a potent non-peptide antagonist at tachykinin NK2 receptors. Eur J Pharmacol. 1995 Jan 16;272(2-3):241-8.
REF 31Role of D-tryptophan for affinity of MEN 10207 tachykinin antagonist at NK2 receptors. Peptides. 1991 Sep-Oct;12(5):1015-8.
REF 32MEN 10,627, a novel polycyclic peptide antagonist of tachykinin NK2 receptors. J Pharmacol Exp Ther. 1994 Dec;271(3):1489-500.
REF 33Discovery of novel, orally active dual NK1/NK2 antagonists. Bioorg Med Chem Lett. 2001 Oct 22;11(20):2769-73.
REF 34Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800015341)
REF 35Characterisation, CNS distribution and function of NK2 receptors studied using potent NK2 receptor antagonists. Regul Pept. 1993 Jul 2;46(1-2):9-19.
REF 36Synthesis and characterization of selective fluorescent ligands for the neurokinin NK2 receptor. J Med Chem. 1994 Jun 24;37(13):1991-5.
REF 37Antagonist profile of ibodutant at the tachykinin NK2 receptor in guinea pig isolated bronchi. Eur J Pharmacol. 2013 Oct 24. pii: S0014-2999(13)00788-7.
REF 38Pharmacology of an original and selective nonpeptide antagonist ligand for the human tachykinin NK2 receptor. Eur J Pharmacol. 2005 Jun 1;516(2):104-11.
REF 39Characterization of the binding sites of [3H]SR 48968, a potent nonpeptide radioligand antagonist of the neurokinin-2 receptor. Biochem Biophys Res Commun. 1993 Mar 31;191(3):1172-7.
REF 40Occurrence and pharmacological characterization of four human tachykinin NK2 receptor variants. Biochem Pharmacol. 2008 Aug 15;76(4):476-81. Epub 2008 Jun 13.
REF 41Multifaceted approach to determine the antagonist molecular mechanism and interaction of ibodutant ([1-(2-phenyl-1R-[[1-(tetrahydropyran-4-ylmethyl)-piperidin-4-ylmethyl]-carbamoyl]-ethylcarbamoyl)-cyclopentyl]-amide) at the human tachykinin NK2 receptor. J Pharmacol Exp Ther. 2009 May;329(2):486-95. Epub 2009 Feb 13.
REF 42Characterization of species-related differences in the pharmacology of tachykinin NK receptors 1, 2 and 3. Biochem Pharmacol. 2009 May 1;77(9):1522-30. Epub 2009 Feb 6.
REF 43SCH 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 44Antagonists at the neurokinin receptors--recent patent literature. IDrugs. 2003 Aug;6(8):758-72.
REF 45Pharmacologic evaluation of neurokinin-2 receptor antagonists in the guinea pig respiratory tract. Am J Vet Res. 2004 Jul;65(7):984-91.
REF 46Pharmacokinetics and metabolism of a sulphamide NK2 antagonist in rat, dog and human. Xenobiotica. 2000 Jun;30(6):627-42.
REF 47Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800017162)
REF 48Effect of YM-44781, YM-44778 and YM-49598, novel tachykinin antagonists, in a drug-induced bladder contraction model. Pharmacology. 2002 May;65(2):96-102.
REF 49Pharmacological characterization of a new class of nonpeptide neurokinin A antagonists that demonstrate species selectivity. J Pharmacol Exp Ther. 1995 Sep;274(3):1216-21.
REF 50Tachykinin NK2 receptor antagonists. A patent review (2006 - 2010). Expert Opin Ther Pat. 2012 Jan;22(1):57-77.
REF 51Expression of rat NK-2 (neurokinin A) receptor in E. coli. Receptors Channels. 1994;2(4):295-302.
REF 52Structure-activity relationships of neurokinin A (4-10) at the human tachykinin NK(2) receptor: the role of natural residues and their chirality. Biochem Pharmacol. 2001 Jan 1;61(1):55-60.

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