Target Information
| Target General Information | Top | |||||
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| Target ID |
T29683
(Former ID: TTDC00117)
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| Target Name |
Neuromedin-K receptor (TACR3)
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| Synonyms |
Tachykinin receptor 3; TACR3; Neuromedin K receptor; Neurokinin-3 receptor; Neurokinin B receptor; NKR; NK-3R; NK-3 receptor
Click to Show/Hide
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| Gene Name |
TACR3
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| Target Type |
Successful target
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[1] | ||||
| Disease | [+] 1 Target-related Diseases | + | ||||
| 1 | Menopausal disorder [ICD-11: GA30] | |||||
| 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.
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| BioChemical Class |
GPCR rhodopsin
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| UniProt ID | ||||||
| Sequence |
MATLPAAETWIDGGGGVGADAVNLTASLAAGAATGAVETGWLQLLDQAGNLSSSPSALGL
PVASPAPSQPWANLTNQFVQPSWRIALWSLAYGVVVAVAVLGNLIVIWIILAHKRMRTVT NYFLVNLAFSDASMAAFNTLVNFIYALHSEWYFGANYCRFQNFFPITAVFASIYSMTAIA VDRYMAIIDPLKPRLSATATKIVIGSIWILAFLLAFPQCLYSKTKVMPGRTLCFVQWPEG PKQHFTYHIIVIILVYCFPLLIMGITYTIVGITLWGGEIPGDTCDKYHEQLKAKRKVVKM MIIVVMTFAICWLPYHIYFILTAIYQQLNRWKYIQQVYLASFWLAMSSTMYNPIIYCCLN KRFRAGFKRAFRWCPFIKVSSYDELELKTTRFHPNRQSSMYTVTRMESMTVVFDPNDADT TRSSRKKRATPRDPSFNGCSRRNSKSASATSSFISSPYTSVDEYS Click to Show/Hide
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| 3D Structure | Click to Show 3D Structure of This Target | AlphaFold | ||||
| HIT2.0 ID | T52S7S | |||||
| Drugs and Modes of Action | Top | |||||
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| Approved Drug(s) | [+] 1 Approved Drugs | + | ||||
| 1 | Fezolinetant | Drug Info | Approved | Hot flushes | [2] | |
| Clinical Trial Drug(s) | [+] 5 Clinical Trial Drugs | + | ||||
| 1 | Elinzanetant | Drug Info | Phase 3 | Hot flushes | [3] | |
| 2 | AZD2624 | Drug Info | Phase 2 | Multiple sclerosis | [4] | |
| 3 | Senktide | Drug Info | Phase 2 | Ischemic stroke | [5], [6] | |
| 4 | Talnetant | Drug Info | Phase 2 | Schizophrenia | [7] | |
| 5 | GSK1144814 | Drug Info | Phase 1 | Schizophrenia | [8] | |
| Discontinued Drug(s) | [+] 3 Discontinued Drugs | + | ||||
| 1 | Osanetant | Drug Info | Discontinued in Phase 2b | Schizoaffective disorder | [9], [10] | |
| 2 | CS-003 | Drug Info | Discontinued in Phase 2 | Chronic obstructive pulmonary disease | [11] | |
| 3 | SSR-146977 | Drug Info | Discontinued in Phase 1 | Psychotic disorder | [12], [13] | |
| Preclinical Drug(s) | [+] 1 Preclinical Drugs | + | ||||
| 1 | SB222200 | Drug Info | Preclinical | Schizoaffective disorder | [14], [15] | |
| Mode of Action | [+] 4 Modes of Action | + | ||||
| Antagonist | [+] 14 Antagonist drugs | + | ||||
| 1 | Fezolinetant | Drug Info | [16] | |||
| 2 | Elinzanetant | Drug Info | [17] | |||
| 3 | Talnetant | Drug Info | [1], [21], [22] | |||
| 4 | Osanetant | Drug Info | [1], [21], [22], [24] | |||
| 5 | CS-003 | Drug Info | [11] | |||
| 6 | SSR-146977 | Drug Info | [25] | |||
| 7 | SB222200 | Drug Info | [26], [27], [28] | |||
| 8 | GR138676 | Drug Info | [32] | |||
| 9 | GSK-172981 | Drug Info | [24] | |||
| 10 | N',2-diphenylquinoline-4-carbohydrazide | Drug Info | [30] | |||
| 11 | N',2-diphenylquinoline-4-carbohydrazide 8m | Drug Info | [34] | |||
| 12 | PD 154740 | Drug Info | [37] | |||
| 13 | R-820 | Drug Info | [19] | |||
| 14 | SCH 206272 | Drug Info | [39] | |||
| Modulator | [+] 2 Modulator drugs | + | ||||
| 1 | AZD2624 | Drug Info | [18] | |||
| 2 | GSK1144814 | Drug Info | [23] | |||
| Agonist | [+] 4 Agonist drugs | + | ||||
| 1 | Senktide | Drug Info | [19], [20] | |||
| 2 | eledoisin | Drug Info | [31] | |||
| 3 | kassinin | Drug Info | [33] | |||
| 4 | neurokinin A | Drug Info | [35] | |||
| Inhibitor | [+] 7 Inhibitor drugs | + | ||||
| 1 | 2-phenyl-N-(1-phenylethyl)quinoline-4-carboxamide | Drug Info | [29] | |||
| 2 | 3-methoxy-N',2-diphenylquinoline-4-carbohydrazide | Drug Info | [30] | |||
| 3 | N-phenethyl-2-phenylquinoline-4-carboxamide | Drug Info | [29] | |||
| 4 | NEUROKININ B | Drug Info | [36] | |||
| 5 | PD-157672 | Drug Info | [36] | |||
| 6 | PD-160946 | Drug Info | [38] | |||
| 7 | PD-161182 | Drug Info | [38] | |||
| Cell-based Target Expression Variations | Top | |||||
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| Cell-based Target Expression Variations | ||||||
| Different Human System Profiles of Target | Top |
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Human Similarity Proteins
of target is determined by comparing the sequence similarity of all human proteins with the target based on BLAST. The similarity proteins for a target are defined as the proteins with E-value < 0.005 and outside the protein families of the target.
A target that has fewer human similarity proteins outside its family is commonly regarded to possess a greater capacity to avoid undesired interactions and thus increase the possibility of finding successful drugs
(Brief Bioinform, 21: 649-662, 2020).
Human Pathway Affiliation
of target is determined by the life-essential pathways provided on KEGG database. The target-affiliated pathways were defined based on the following two criteria (a) the pathways of the studied target should be life-essential for both healthy individuals and patients, and (b) the studied target should occupy an upstream position in the pathways and therefore had the ability to regulate biological function.
Targets involved in a fewer pathways have greater likelihood to be successfully developed, while those associated with more human pathways increase the chance of undesirable interferences with other human processes
(Pharmacol Rev, 58: 259-279, 2006).
Biological Network Descriptors
of target is determined based on a human protein-protein interactions (PPI) network consisting of 9,309 proteins and 52,713 PPIs, which were with a high confidence score of ≥ 0.95 collected from STRING database.
The network properties of targets based on protein-protein interactions (PPIs) have been widely adopted for the assessment of target’s druggability. Proteins with high node degree tend to have a high impact on network function through multiple interactions, while proteins with high betweenness centrality are regarded to be central for communication in interaction networks and regulate the flow of signaling information
(Front Pharmacol, 9, 1245, 2018;
Curr Opin Struct Biol. 44:134-142, 2017).
Human Similarity Proteins
Human Pathway Affiliation
Biological Network Descriptors
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| KEGG Pathway | Pathway ID | Affiliated Target | Pathway Map |
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| Calcium signaling pathway | hsa04020 | Affiliated Target |
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| Class: Environmental Information Processing => Signal transduction | Pathway Hierarchy | ||
| Neuroactive ligand-receptor interaction | hsa04080 | Affiliated Target |
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| Class: Environmental Information Processing => Signaling molecules and interaction | Pathway Hierarchy | ||
| Degree | 1 | Degree centrality | 1.07E-04 | Betweenness centrality | 0.00E+00 |
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| Closeness centrality | 1.24E-01 | Radiality | 1.07E+01 | Clustering coefficient | 0.00E+00 |
| Neighborhood connectivity | 3.00E+00 | Topological coefficient | 1.00E+00 | Eccentricity | 15 |
| Download | Click to Download the Full PPI Network of This Target | ||||
| Chemical Structure based Activity Landscape of Target | Top |
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| Drug Property Profile of Target | Top | |
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| (1) Molecular Weight (mw) based Drug Clustering | (2) Octanol/Water Partition Coefficient (xlogp) based Drug Clustering | |
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| (3) Hydrogen Bond Donor Count (hbonddonor) based Drug Clustering | (4) Hydrogen Bond Acceptor Count (hbondacc) based Drug Clustering | |
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| (5) Rotatable Bond Count (rotbonds) based Drug Clustering | (6) Topological Polar Surface Area (polararea) based Drug Clustering | |
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| "RO5" indicates the cutoff set by lipinski's rule of five; "D123AB" colored in GREEN denotes the no violation of any cutoff in lipinski's rule of five; "D123AB" colored in PURPLE refers to the violation of only one cutoff in lipinski's rule of five; "D123AB" colored in BLACK represents the violation of more than one cutoffs in lipinski's rule of five | ||
| Co-Targets | Top | |||||
|---|---|---|---|---|---|---|
| Co-Targets | ||||||
| Target Poor or Non Binders | Top | |||||
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| Target Poor or Non Binders | ||||||
| Target Profiles in Patients | Top | |||||
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| Target Expression Profile (TEP) | ||||||
| Target Affiliated Biological Pathways | Top | |||||
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| KEGG Pathway | [+] 2 KEGG Pathways | + | ||||
| 1 | Calcium signaling pathway | |||||
| 2 | Neuroactive ligand-receptor interaction | |||||
| Reactome | [+] 1 Reactome Pathways | + | ||||
| 1 | G alpha (q) signalling events | |||||
| WikiPathways | [+] 4 WikiPathways | + | ||||
| 1 | Gastrin-CREB signalling pathway via PKC and MAPK | |||||
| 2 | Peptide GPCRs | |||||
| 3 | GPCR ligand binding | |||||
| 4 | GPCR downstream signaling | |||||
| Target-Related Models and Studies | Top | |||||
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| Target Validation | ||||||
| References | Top | |||||
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| REF 1 | Pharmacological characterization of senktide-induced tail whips. Neuropharmacology. 2010 Jan;58(1):259-67. | |||||
| REF 2 | FDA Approved Drug Products from FDA Official Website. | |||||
| REF 3 | ClinicalTrials.gov (NCT05099159) A Double-blind, Randomized, Placebo-controlled Multicenter Study to Investigate Efficacy and Safety of Elinzanetant for the Treatment of Vasomotor Symptoms Over 26 Weeks in Postmenopausal Women. U.S.National Institutes of Health. | |||||
| REF 4 | Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800038259) | |||||
| REF 5 | Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA) | |||||
| REF 6 | Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA) | |||||
| REF 7 | ClinicalTrials.gov (NCT00300963) Effect Of Talnetant Versus Risperidone Versus Placebo On Psychotic Symptoms In Schizophrenic Patients in GlaxoSmithKline. | |||||
| REF 8 | ClinicalTrials.gov (NCT01090440) Pharmacokinetics, Effect of Food, Safety and Tolerability of a New Tablet Formulation of GSK1144814 in Healthy Subjects (MNK112891) in GlaxoSmithKline. | |||||
| REF 9 | URL: 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 10 | The pipeline and future of drug development in schizophrenia. Mol Psychiatry. 2007 Oct;12(10):904-22. | |||||
| REF 11 | Emerging drugs for the treatment of chronic obstructive pulmonary disease. Expert Opin Emerg Drugs. 2006 May;11(2):275-91. | |||||
| REF 12 | URL: 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 13 | Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800014351) | |||||
| REF 14 | URL: 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 15 | Nonpeptide 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 16 | Fezolinetant for treatment of moderate-to-severe vasomotor symptoms associated with menopause (SKYLIGHT 1): a phase 3 randomised controlled study. Lancet. 2023 Apr 1;401(10382):1091-1102. | |||||
| REF 17 | Elinzanetant (NT-814), a Neurokinin 1,3 Receptor Antagonist, Reduces Estradiol and Progesterone in Healthy Women. J Clin Endocrinol Metab. 2021 Jul 13;106(8):e3221-e3234. | |||||
| REF 18 | The selective neurokinin 3 antagonist AZD2624 does not improve symptoms or cognition in schizophrenia: a proof-of-principle study.J Clin Psychopharmacol.2014 Apr;34(2):199-204. | |||||
| REF 19 | Implication 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 20 | Neurokinin-3 receptors modulate dopamine cell function and alter the effects of 6-hydroxydopamine. Brain Res. 1995 Oct 9;695(1):19-24. | |||||
| REF 21 | The tachykinin NK3 receptor agonist senktide induces locomotor activity in male Mongolian gerbils. Eur J Pharmacol. 2008 Dec 14;600(1-3):87-92. | |||||
| REF 22 | Augmentation of antipsychotic-induced neurochemical changes by the NK3 receptor antagonist talnetant (SB-223412). Neuropharmacology. 2009 Feb;56(2):342-9. | |||||
| REF 23 | Pharmacokinetics and central nervous system effects of the novel dual NK1 /NK3 receptor antagonist GSK1144814 in alcohol-intoxicated volunteers.Br J Clin Pharmacol.2013 May;75(5):1328-39. | |||||
| REF 24 | URL: 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 25 | Biochemical 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 26 | Evidence 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. | |||||
| REF 27 | Neurokinin 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. | |||||
| REF 28 | Substance P depolarizes striatal projection neurons and facilitates their glutamatergic inputs. J Physiol. 2008 Apr 15;586(8):2143-55. | |||||
| REF 29 | Virtual screening to identify novel antagonists for the G protein-coupled NK3 receptor. J Med Chem. 2010 Nov 25;53(22):8080-8. | |||||
| REF 30 | N',2-diphenylquinoline-4-carbohydrazide based NK3 receptor antagonists. Bioorg Med Chem Lett. 2006 Nov 15;16(22):5748-51. | |||||
| REF 31 | Molecular characterisation, expression and localisation of human neurokinin-3 receptor. FEBS Lett. 1992 Mar 24;299(1):90-5. | |||||
| REF 32 | GR138676, a novel peptidic tachykinin antagonist which is potent at NK3 receptors. Neuropeptides. 1994 Dec;27(6):333-41. | |||||
| REF 33 | The 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 34 | N',2-diphenylquinoline-4-carbohydrazide based NK3 receptor antagonists II. Bioorg Med Chem Lett. 2006 Nov 15;16(22):5752-6. | |||||
| REF 35 | Molecular and pharmacological characterization of the murine tachykinin NK(3) receptor. Eur J Pharmacol. 2001 Feb 16;413(2-3):143-50. | |||||
| REF 36 | The 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 37 | Two classes of structurally different antagonists display similar species preference for the human tachykinin neurokinin3 receptor. Mol Pharmacol. 1995 Oct;48(4):711-6. | |||||
| REF 38 | The development of a novel series of non-peptide tachykinin NK3 receptor selective antagonists, Bioorg. Med. Chem. Lett. 5(16):1773-1778 (1995). | |||||
| REF 39 | SCH 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. | |||||
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