Details of the Drug Therapeutic Target (DTT)

General Information of Drug Therapeutic Target (DTT) (ID: TTBPGLU)

• DTT Name: Neuromedin-K receptor (TACR3)
• Synonyms: Tachykinin receptor 3; TACR3; Neuromedin K receptor; Neurokinin-3 receptor; Neurokinin B receptor; NKR; NK-3R; NK-3 receptor
• Gene Name: TACR3
• DTT Type: Clinical trial target; [1]
• BioChemical Class: GPCR rhodopsin
• UniProt ID: NK3R_HUMAN
• TTD ID: T29683
• Sequence:
  MATLPAAETWIDGGGGVGADAVNLTASLAAGAATGAVETGWLQLLDQAGNLSSSPSALGL
  PVASPAPSQPWANLTNQFVQPSWRIALWSLAYGVVVAVAVLGNLIVIWIILAHKRMRTVT
  NYFLVNLAFSDASMAAFNTLVNFIYALHSEWYFGANYCRFQNFFPITAVFASIYSMTAIA
  VDRYMAIIDPLKPRLSATATKIVIGSIWILAFLLAFPQCLYSKTKVMPGRTLCFVQWPEG
  PKQHFTYHIIVIILVYCFPLLIMGITYTIVGITLWGGEIPGDTCDKYHEQLKAKRKVVKM
  MIIVVMTFAICWLPYHIYFILTAIYQQLNRWKYIQQVYLASFWLAMSSTMYNPIIYCCLN
  KRFRAGFKRAFRWCPFIKVSSYDELELKTTRFHPNRQSSMYTVTRMESMTVVFDPNDADT
  TRSSRKKRATPRDPSFNGCSRRNSKSASATSSFISSPYTSVDEYS
• 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.
• KEGG Pathway:
  Calcium signaling pathway (hsa04020)
  Neuroactive ligand-receptor interaction (hsa04080)
• Reactome Pathway: G alpha (q) signalling events (R-HSA-416476)

Molecular Interaction Atlas (MIA) of This DTT

1 Approved Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Fezolinetant	DMHDQZD	Hot flushes	GA30	Approved	[2]

5 Clinical Trial Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Elinzanetant	DMC6EFI	Hot flushes	GA30	Phase 3	[3]
AZD2624	DMZLGQV	Multiple sclerosis	8A40	Phase 2	[4]
Senktide	DMOH8LD	Epilepsy	8A60-8A68	Phase 2	[5]
Talnetant	DMQKZDT	Schizophrenia	6A20	Phase 2	[1]
GSK1144814	DMK3S9J	Alcohol dependence	6C40.2	Phase 1	[6]

3 Discontinued Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Osanetant	DMMT4PB	Schizoaffective disorder	6A21	Discontinued in Phase 2b	[1]
CS-003	DM1AEVT	Chronic obstructive pulmonary disease	CA22	Discontinued in Phase 2	[7]
SSR-146977	DMR9JA8	Psychotic disorder	6A20-6A25	Discontinued in Phase 1	[8]

1 Preclinical Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
SB222200	DM6X0PZ	Schizoaffective disorder	6A21	Preclinical	[9]

17 Investigative Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
2-phenyl-N-(1-phenylethyl)quinoline-4-carboxamide	DMNOE0V	Discovery agent	N.A.	Investigative	[10]
3-methoxy-N',2-diphenylquinoline-4-carbohydrazide	DMZ9MQ5	Discovery agent	N.A.	Investigative	[11]
eledoisin	DMEOJ9W	Discovery agent	N.A.	Investigative	[12]
GR138676	DMW8YDR	Discovery agent	N.A.	Investigative	[13]
GSK-172981	DM9IZNP	Asthma	CA23	Investigative	[14]
kassinin	DMMIA38	Discovery agent	N.A.	Investigative	[15]
N',2-diphenylquinoline-4-carbohydrazide	DMWKRJX	Discovery agent	N.A.	Investigative	[11]
N',2-diphenylquinoline-4-carbohydrazide 8m	DMNJA3C	Discovery agent	N.A.	Investigative	[16]
N-phenethyl-2-phenylquinoline-4-carboxamide	DM4G6LJ	Discovery agent	N.A.	Investigative	[10]
neurokinin A	DM9UXRP	Discovery agent	N.A.	Investigative	[17]
NEUROKININ B	DM5O2MJ	Discovery agent	N.A.	Investigative	[18]
PD 154740	DM5GTHE	Discovery agent	N.A.	Investigative	[19]
PD-157672	DMHI8C9	Discovery agent	N.A.	Investigative	[18]
PD-160946	DMZYIKR	Discovery agent	N.A.	Investigative	[20]
PD-161182	DM8NV2E	Discovery agent	N.A.	Investigative	[20]
R-820	DMHX9CT	Discovery agent	N.A.	Investigative	[5]
SCH 206272	DMD1M24	Discovery agent	N.A.	Investigative	[21]

Molecular Expression Atlas (MEA) of This DTT

Disease Name	ICD 11	Studied Tissue	p-value	Fold-Change	Z-score
Chronic obstructive pulmonary disease	CA23	Lung tissue	2.82E-02	0.09	0.41
Chronic obstructive pulmonary disease	CA23	Small airway epithelium	6.76E-01	-0.01	-0.04
Schizophrenia	6A20	Pre-frontal cortex	3.59E-01	0.04	0.12
Schizophrenia	6A20	Superior temporal cortex	5.19E-01	-4.10E-03	-0.03
Asthma	CA23	Nasal and bronchial airway	3.69E-02	-0.08	-0.26

References

• [1] Pharmacological characterization of senktide-induced tail whips. Neuropharmacology. 2010 Jan;58(1):259-67.
• [2] 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.
• [3] 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.
• [4] 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.
• [5] 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.
• [6] 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.
• [7] Emerging drugs for the treatment of chronic obstructive pulmonary disease. Expert Opin Emerg Drugs. 2006 May;11(2):275-91.
• [8] 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.
• [9] 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.
• [10] Virtual screening to identify novel antagonists for the G protein-coupled NK3 receptor. J Med Chem. 2010 Nov 25;53(22):8080-8.
• [11] N',2-diphenylquinoline-4-carbohydrazide based NK3 receptor antagonists. Bioorg Med Chem Lett. 2006 Nov 15;16(22):5748-51.
• [12] Molecular characterisation, expression and localisation of human neurokinin-3 receptor. FEBS Lett. 1992 Mar 24;299(1):90-5.
• [13] GR138676, a novel peptidic tachykinin antagonist which is potent at NK3 receptors. Neuropeptides. 1994 Dec;27(6):333-41.
• [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. (Target id: 362).
• [15] 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.
• [16] N',2-diphenylquinoline-4-carbohydrazide based NK3 receptor antagonists II. Bioorg Med Chem Lett. 2006 Nov 15;16(22):5752-6.
• [17] Molecular and pharmacological characterization of the murine tachykinin NK(3) receptor. Eur J Pharmacol. 2001 Feb 16;413(2-3):143-50.
• [18] 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).
• [19] Two classes of structurally different antagonists display similar species preference for the human tachykinin neurokinin3 receptor. Mol Pharmacol. 1995 Oct;48(4):711-6.
• [20] The development of a novel series of non-peptide tachykinin NK3 receptor selective antagonists, Bioorg. Med. Chem. Lett. 5(16):1773-1778 (1995).
• [21] 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.