Therapeutic Targets Database
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TTD Target ID: TTDS00194

Target Information
NameSubstance-P receptor    
Type of targetSuccessful target    
SynonymsNK-1 receptor    
NK-1R    
Neurokinin 1 receptor    
SPR    
Substance P receptor    
Tachykinin 1 receptor    
Tachykinin neurokinin 1 receptor    
Tachykinin receptor 1    
DiseaseAnalgesics    [1]
Asthma    [2]
Mood [affective] disorders    [3]
Neuropathic pain    [1]
Visceral pain    [4]
Drug(s)AprepitantApprovedNausea and vomiting[5]
OrvepitantPhase IIDepression & anxiety[6]
GSK1144814Phase ISchizophrenia[6]
AZD2624Discontinued in Phase IISchizophrenia[7]
CS-003Discontinued in Phase IIChronic obstructive pulmonary disease[8]
CasopitantWithdrawn in marketing authorisation application to European Medicines AgencyChemotherapy-induced nausea and vomiting[9]
DA-5018Suspended in Phase II in Dong-A 2009 PipelineDiabetic neuropathy, postherpetic neuralgia[10]
DNK-333Discontinued in Phase IIIrritable Bowel Syndrome With Diarrhea (IBS-D), Asthma[8]
EzlopitantSuspended in Phase II in Pfizer 2010 PipelineEmesis, irritable bowel syndrome[11]
GSK 679769Discontinued in Phase IIIncontinence, anxiety disorder, chemotherapyinduced emesis, major depressive disorder[11]
GSK424887Suspended in Phase I in GSK 2009 ReportDepression & anxiety[6]
L-759274Discontinued in Phase IIISevere Mood Disorders, Depression[9]
R 673Discontinued in Phase IIDepression[9]
SLV-317Discontinued in Phase IIrritable bowel syndrome[12]
SLV-323Suspended in Phase IIrritable bowel syndrome, chemotherapyinduced emesis, gastric motility disorder[11]
TAK-637Discontinued in Phase IIDepression[9]
VestipitantDiscontinued in Phase IIAnxiety disorder, chemotherapyinduced emesis, dyspepsia, major depressive disorder[13]
Zunrisa/RezonicDiscontinued the regulatory filingsChemotherapy-induced & postoperative nausea & vomiting[6]
BioChemical ClassG-protein coupled receptor (rhodopsin family)    
PathwayCalcium signaling pathway
Neuroactive ligand-receptor interaction
UniProt IDP25103
FunctionThis is a receptor for the tachykinin neuropeptide substance p. It is probably associated with G proteins that activate a phosphatidylinositol-calcium second messenger system.    
SequenceMDNVLPVDSDLSPNISTNTSEPNQFVQPAWQIVLWAAAYTVIVVTSVVGNVVVMWIILAH KRMRTVTNYFLVNLAFAEASMAAFNTVVNFTYAVHNEWYYGLFYCKFHNFFPIAAVFASI YSMTAVAFDRYMAIIHPLQPRLSATATKVVICVIWVLALLLAFPQGYYSTTETMPSRVVC MIEWPEHPNKIYEKVYHICVTVLIYFLPLLVIGYAYTVVGITLWASEIPGDSSDRYHEQV SAKRKVVKMMIVVVCTFAICWLPFHIFFLLPYINPDLYLKKFIQQVYLAIMWLAMSSTMY NPIIYCCLNDRFRLGFKHAFRCCPFISAGDYEGLEMKSTRYLQTQGSVYKVSRLETTIST VVGAHEEEPEDGPKATPSSLDLTSNCSSRSDSKTMTESFSFSSNVLS
Related US Patent6,207,678
6,235,735
6,258,800
6,265,614
6,288,225
6,319,917
6,333,042
6,339,094
6,358,994
6,365,602
6,372,754
6,403,582
6,403,601
6,407,106
6,432,952
6,432,953
6,436,928
6,452,001
6,472,418
6,476,077
6,479,518
6,482,829
6,500,818
6,518,273
6,525,073
6,534,502
6,564,152
6,569,872
6,576,638
6,583,142
6,586,432
6,620,438
6,635,630
6,638,930
6,649,614
6,664,253
6,676,950
6,696,042
6,727,244
Target ValidationClick to Find Target Validation Information.    
Inhibitor (D)-Phe-[14]
(D)-Phe-[14]
(L)-Phe-[14]
2-Phenyl-3- (1-phenyl-ethoxy)-piperidine[15]
3,6-Diphenyl-1-oxa-7-aza-spiro[4.5]decane[16]
3-Benzyloxy-2-phenyl-piperidine[15]
4- (4-butylpiperidin-1-yl)-1-o-tolylbutan-1-one[17]
7-METHYL-8-OXO-5-P-TOLYL-7,8-DIHYDRO-[1,7]NAPHTHYRIDINE-6-CARBOXYLIC ACID (3,5-BIS-TRIFLUOROMETHYL-BENZYL)-METHYL-AMIDE [18]
7-METHYL-8-OXO-5-P-TOLYL-7,8-DIHYDRO-[1,7]NAPHTHYRIDINE-6-CARBOXYLIC ACID (S)-[[18]
7-METHYL-8-OXO-5-P-TOLYL-7,8-DIHYDRO-[1,7]NAPHTHYRIDINE-6-CARBOXYLIC ACID (S)-[[18]
Ac-Phe-Phe-NH2[14]
Arg-Pro-Lys-Pro-Ala-Gln-Phe-Phe-Gly-Leu-Met-NH2[19]
Arg-Pro-Lys-Pro-Ala-Ser-Phe-Phe-Gly-Leu-Met-NH2[19]
Arg-Pro-Lys-Pro-Gln-Ser-Phe-Phe-Gly-Leu-Met-NH2[19]
CP-96345[20]
CP-99994[21]
ENDOMORPHIN 2[14]
H-Ala-Pro-Phe-Phe-NH2[14]
H-Arg-Pro-Lys-Pro-Gln-Gln-Phe-OH[14]
H-Leu-Phe-NH2[14]
H-Phe-NH2[14]
H-Phe-Phe-NH2[14]
H-Pro-Phe-Phe-NH2[14]
H-Tyr (OMe)-Phe[14]
H-Tyr-Ala-Phe-Phe-NH2[14]
H-Tyr-D-Ala-Gly Phe-Pro-Leu-Trp-O-3,5-Bzl (CF3)2[22]
H-Tyr-D-Ala-Gly-Phe-Pro-Leu-Trp-NH-3,5-Bzl (CF3)2[22]
H-Tyr-D-Ala-Gly-Phe-Pro-Leu-Trp-NH-Bzl[22]
H-Tyr-D-Ala-Gly-Phe-Pro-Leu-Trp-NMe-3,5-Bzl (CF3)2[22]
H-Tyr-D-Ala-Gly-Phe-Pro-Leu-Trp-NMe-Bzl[22]
H-Tyr-D-Ala-Gly-Phe-Pro-Leu-Trp-O-Bzl[22]
H-Tyr-Pro-Ala-Phe-NH2[14]
H-Tyr-Pro-Phe-Ala-NH2[14]
H-Tyr-Pro-Phe-Phe-OH[14]
L-708568[23]
L-732138[24]
L-732138[25]
L-733060[15]
L-736281[26]
L-741671[26]
MDL-28163[27]
Pro-Lys-Pro-Gln-Gln-Phe-Phe-Gly-Leu-Met-NH2[19]
R-226161[28]
SCH-388714[29]
SPANTIDE[30]
SUBSTANCE P[31]
Substance P[32]
Tyr-D-Ala-Gly-Phe-Met-Pro-Leu-Trp-NH-Bzl[33]
[Sar9,Met (O2)11]-SP[34]
AgonistSeptide[35]
AntagonistAZD2624[7]
Aprepitant[5]
CI-1021[1]
CJ 11,974-01[36]
CP-100263[11]
CP-122721[37]
CP-99,994[1]
CS-003[8]
Casopitant[9]
DA-5018[10]
DNK-333[8]
Ezlopitant[11]
GSK 679769[11]
GSK1144814[6]
GSK424887[6]
L-759274[9]
MK-869[37]
Orvepitant[6]
R 673[9]
SLV-317[12]
SSR240600[38]
TAK-637[9]
Vestipitant[13]
Zunrisa/Rezonic[6]
ModulatorSLV-323[11]
MultitargetCS-003[8]
DNK-333[8]
GSK1144814[6]
Cross References 3D Structure
Related Literature
On-Line Medical Dictionary
Ref 1Gabapentin and the neurokinin(1) receptor antagonist CI-1021 act synergistically in two rat models of neuropathic pain. J Pharmacol Exp Ther. 2002 Nov;303(2):730-5. To Reference
Ref 2The role of neuroeffector mechanisms in the pathogenesis of asthma. Curr Allergy Asthma Rep. 2001 Mar;1(2):134-43. To Reference
Ref 3Substance P and affective disorders: new treatment opportunities by neurokinin 1 receptor antagonists? Neuropsychobiology. 2002;45 Suppl 1:2-6. To Reference
Ref 4NK1 receptor-mediated mechanisms regulate colonic hypersensitivity in the guinea pig. Pharmacol Biochem Behav. 2003 Mar;74(4):1005-13. To Reference
Ref 5Potent, brain-penetrant, hydroisoindoline-based human neurokinin-1 receptor antagonists. J Med Chem. 2009 May 14;52(9):3039-46. To Reference
Ref 6GSK. Product Development Pipeline. February 2009. To Reference
Ref 7AstraZeneca. Product Development Pipeline. January 29 2009. To Reference
Ref 8Emerging drugs for the treatment of chronic obstructive pulmonary disease. Expert Opin Emerg Drugs. 2006 May;11(2):275-91. To Reference
Ref 9Novel drugs and therapeutic targets for severe mood disorders. Neuropsychopharmacology. 2008 Aug;33(9):2080-92. Epub 2008 Jan 2. To Reference
Ref 10Emerging drugs in neuropathic pain. Expert Opin Emerg Drugs. 2007 Mar;12(1):113-26. To Reference
Ref 11Emerging drugs for chemotherapy-induced emesis. Expert Opin Emerg Drugs. 2006 Mar;11(1):137-51. To Reference
Ref 12Emerging drugs for irritable bowel syndrome. Expert Opin Emerg Drugs. 2006 May;11(2):293-313. To Reference
Ref 13Emerging drugs for eating disorder treatment. Expert Opin Emerg Drugs. 2006 May;11(2):315-36. To Reference
Ref 14J Med Chem. 2010 Mar 25;53(6):2383-9.Discovery of dipeptides with high affinity to the specific binding site for substance P1-7. To Reference
Ref 15Bioorg. Med. Chem. Lett. 7(23):2959-2962 (1997) To Reference
Ref 16Bioorg Med Chem Lett. 2002 Oct 7;12(19):2719-22.Spirocyclic NK(1) antagonists II: [4.5]-spiroethers. To Reference
Ref 17J 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. To Reference
Ref 18J Med Chem. 1998 Oct 22;41(22):4232-9.Axially chiral N-benzyl-N,7-dimethyl-5-phenyl-1, 7-naphthyridine-6-carboxamide derivatives as tachykinin NK1 receptor antagonists: determination of the absolute stereochemical requirements. To Reference
Ref 19J Med Chem. 2007 Dec 27;50(26):6501-6. Epub 2007 Dec 8.Conformational comparisons of a series of tachykinin peptide analogs. To Reference
Ref 20Bioorg. Med. Chem. Lett. 4(6):839-842 (1994) To Reference
Ref 21Bioorg Med Chem Lett. 2007 Dec 15;17(24):6887-90. Epub 2007 Oct 5.Stereoselective synthesis of a novel 2-aza-7-oxabicyclo[3.3.0]octane as neurokinin-1 receptor antagonist. To Reference
Ref 22J Med Chem. 2008 Mar 13;51(5):1369-76. Epub 2008 Feb 12.A structure-activity relationship study and combinatorial synthetic approach of C-terminal modified bifunctional peptides that are delta/mu opioid receptor agonists and neurokinin 1 receptor antagonists. To Reference
Ref 23J Med Chem. 1993 Jul 9;36(14):2044-5.N-acyl-L-tryptophan benzyl esters: potent substance P receptor antagonists. To Reference
Ref 24J Med Chem. 2007 Jun 14;50(12):2779-86. Epub 2007 May 22.Design, synthesis, and biological evaluation of novel bifunctional C-terminal-modified peptides for delta/mu opioid receptor agonists and neurokinin-1 receptor antagonists. To Reference
Ref 25Bioorg Med Chem. 2009 Oct 15;17(20):7337-43. Epub 2009 Aug 21.The biological activity and metabolic stability of peptidic bifunctional compounds that are opioid receptor agonists and neurokinin-1 receptor antagonists with a cystine moiety. To Reference
Ref 26J Med Chem. 1996 Jul 19;39(15):2907-14.N-heteroaryl-2-phenyl-3-(benzyloxy)piperidines: a novel class of potent orally active human NK1 antagonists. To Reference
Ref 27J Med Chem. 2005 Oct 20;48(21):6523-43.Designed multiple ligands. An emerging drug discovery paradigm. To Reference
Ref 28Bioorg Med Chem. 2007 Jun 1;15(11):3649-60. Epub 2007 Mar 21.Tricyclic isoxazolines: identification of R226161 as a potential new antidepressant that combines potent serotonin reuptake inhibition and alpha2-adrenoceptor antagonism. To Reference
Ref 29Bioorg Med Chem Lett. 2006 Feb 15;16(4):1065-9. Epub 2005 Nov 14.Cyclic urea derivatives as potent NK1 selective antagonists. Part II: Effects of fluoro and benzylic methyl substitutions. To Reference
Ref 30J Med Chem. 1992 Apr 3;35(7):1273-9.Synthesis and substance P antagonist activity of naphthimidazolium derivatives. To Reference
Ref 31J Med Chem. 1987 Aug;30(8):1529-32.Binary drugs: conjugates of purines and a peptide that bind to both adenosine and substance P receptors. To Reference
Ref 32Bioorg Med Chem Lett. 1998 Feb 3;8(3):281-4.Synthesis and structure-activity relationships of CP-122,721, a second-generation NK-1 receptor antagonist. To Reference
Ref 33J Med Chem. 2008 Oct 23;51(20):6334-47. Epub 2008 Sep 27.The importance of micelle-bound states for the bioactivities of bifunctional peptide derivatives for delta/mu opioid receptor agonists and neurokinin 1 receptor antagonists. To Reference
Ref 34J 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. To Reference
Ref 35Septide: an agonist for the NK1 receptor acting at a site distinct from substance P. Mol Pharmacol. 1994 Feb;45(2):287-93. To Reference
Ref 36Targeting pain-depressed behaviors in preclinical assays of pain and analgesia: drug effects on acetic acid-depressed locomotor activity in ICR mice. Life Sci. 2009 Aug 12;85(7-8):309-15. To Reference
Ref 37A review of drug options in age-related macular degeneration therapy and potential new agents. Expert Opin Pharmacother. 2006 Dec;7(17):2355-68. To Reference
Ref 38SSR240600 [(R)-2-(1-[2-[4-[2-[3,5-bis(trifluoromethyl)phenyl]acetyl]-2-(3,4-dichlorophenyl)-2-morpholinyl]ethyl]- 4-piperidinyl)-2-methylpropanamide], a centrally active nonpeptide antagonist of the tachykinin neurokinin-1 receptor: I. biochemical and pharmacological characterization. J Pharmacol Exp Ther. 2002 Dec;303(3):1171-9. To Reference



 

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Professor in Department of Pharmacy
National University of Singapore, Singapore


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