Target Validation Information | |||||
---|---|---|---|---|---|
Target ID | T52790 | ||||
Target Name | NK-2 receptor | ||||
Target Type | Clinical Trial |
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Drug Potency against Target | A-987306 | Drug Info | IC50 = 5.7 nM | [529789] | |
4-(4-butylpiperidin-1-yl)-1-o-tolylbutan-1-one | Drug Info | Ki < 1000 nM | [531079] | ||
WAY-207024 | Drug Info | Ki = 330 nM | [530005] | ||
L-732138 | Drug Info | Ki = 134 nM | [531023] | ||
DNK-333 | Drug Info | Ki = 5.5 nM | [552275] | ||
CS-003 | Drug Info | Ki = 0.54 nM | [552800] | ||
Ac-Phe-[Orn-Pro-cha-Trp-Arg] | Drug Info | IC50 = 87 nM | [528343] | ||
MEN13510 | Drug Info | Ki = 16 nM | [527392] | ||
Hoo-Phe-Orn-Pro-hle-Pff-Phe-NH2 | Drug Info | IC50 = 710 nM | [528343] | ||
Saredutant | Drug Info | Ki = 0.5 nM | [552360] | ||
Action against Disease Model | DNK-333 | Male Brown Norway rats were imaged prior to and 10, 30 and 60 min after intra-tracheal challenge with capsaicin (30 microg kg(-1)) or vehicle (0.5% ethanol solution). Capsazepine (3.5 mg kg(-1)), DNK333 (10 mg kg(-1)) but not DSCG (10 mg kg(-1)) administered prophylactically were able to block the effect of capsaicin in the airways | [552686] | Drug Info | |
The Effect of Target Knockout, Knockdown or Genetic Variations | Tachykinins such as substance P (SP) and neurokinin A (NKA) acting on neurokinin (NK) receptors modulate the nonadrenergic noncholinergic (NANC) neurotransmission in the gastrointestinal tract of several species, but the information about the mouse small intestine is scanty. Both SP and NKA induced concentration-dependent contractions of ileal segments isolated from wild-type mice that were blocked by NK(1) and NK(2) antagonists, respectively. In contrast, segments isolated from NK(1) receptor (NK(1)-R) knockout mice responded only to elevated concentrations of SP. To reveal the inhibitory NANC (iNANC) responses, tissues were pretreated with atropine and guanethidine. Under these conditions, a tetrodotoxin-sensitive relaxation in response to electrical field stimulation (EFS) was observed. NK(1)-R knockout mice presented a trend toward an increase in iNANC responses, whereas the NK(1)-R antagonist significantly potentiated iNANC relaxation in tissues isolated from wild-type mice. N(G)-nitro-L-arginine methyl ester (100 microM) transformed the relaxant response to EFS into a tetrodotoxin-sensitive, frequency-dependent contraction characteristic of an excitatory NANC (eNANC) system. A NK(1)-R antagonist abolished the contractile responses of the mouse ile uM to EFS, whereas a NK(2) receptor antagonist had a trend toward reducing EFS-induced contraction. TheeNANC component was absent in NK(1)-R knockout mice. Measurement of SP-like immunoreactivity indicated similar amounts of SP per gram of tissue isolated from wild-type and NK(1)-R knockout mice, indicating that the observed differences in response to EFS were not due to a differential peptide content. It is concluded that, in the mouse ile uM, both NK(1) and NK(2) receptors modulated the responses to exogenous tachykinins, whereas NK(1) is the primary tachykinin receptor involved in both iNANC and eNANC transmission. | [529789] | |||
References | |||||
Ref 529789 | J 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 531079 | J 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 530005 | J 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 531023 | J 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 552275 | Dual neurokinin NK(1)/NK(2) antagonists: N-[(R,R)-(E)-1-arylmethyl-3-(2-oxo-azepan-3-yl)carbamoyl]allyl-N-methyl-3,5-bis(trifluoromethyl)benzamides and 3-[N'-3,5-bis(trifluoromethyl)benzoyl-N-arylmethyl-N'-methylhydrazino]-N-[(R)-2-oxo-azepan-3-yl]propionamides. Bioorg Med Chem Lett. 2001 Dec 3;11(23):3081-4. | ||||
Ref 552686 | Capsaicin-induced mucus secretion in rat airways assessed in vivo and non-invasively by magnetic resonance imaging. Br J Pharmacol. 2007 Apr;150(8):1022-30. Epub 2007 Mar 12. | ||||
Ref 552800 | Novel triple neurokinin receptor antagonist CS-003 strongly inhibits neurokinin related responses. Eur J Pharmacol. 2008 May 31;586(1-3):306-12. doi: 10.1016/j.ejphar.2008.02.056. Epub 2008 Mar 4. | ||||
Ref 528343 | Bioorg 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 527392 | Bioorg Med Chem Lett. 2005 Feb 1;15(3):585-8.Generation of a new class of hNK(2) receptor ligands using the 'fragment approach'. | ||||
Ref 528343 | Bioorg 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 552360 | Recent developments in the medicinal chemistry of NK2 receptor antagonists. Curr Top Med Chem. 2003;3(12):1436-45. |
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