Target Information
| Target General Information | Top | |||||
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| Target ID |
T52790
(Former ID: TTDC00090)
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| Target Name |
Substance-K receptor (TACR2)
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| Synonyms |
Tachykinin receptor 2; Tachykinin neurokinin 2 receptor; TACR2; SKR; Neurokinin A receptor; NK-2R; NK-2 receptor
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| Gene Name |
TACR2
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| Target Type |
Clinical trial target
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[1] | ||||
| Disease | [+] 1 Target-related Diseases | + | ||||
| 1 | Irritable bowel syndrome [ICD-11: DD91] | |||||
| 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.
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| BioChemical Class |
GPCR rhodopsin
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| UniProt ID | ||||||
| Sequence |
MGTCDIVTEANISSGPESNTTGITAFSMPSWQLALWATAYLALVLVAVTGNAIVIWIILA
HRRMRTVTNYFIVNLALADLCMAAFNAAFNFVYASHNIWYFGRAFCYFQNLFPITAMFVS IYSMTAIAADRYMAIVHPFQPRLSAPSTKAVIAGIWLVALALASPQCFYSTVTMDQGATK CVVAWPEDSGGKTLLLYHLVVIALIYFLPLAVMFVAYSVIGLTLWRRAVPGHQAHGANLR HLQAMKKFVKTMVLVVLTFAICWLPYHLYFILGSFQEDIYCHKFIQQVYLALFWLAMSST MYNPIIYCCLNHRFRSGFRLAFRCCPWVTPTKEDKLELTPTTSLSTRVNRCHTKETLFMA GDTAPSEATSGEAGRPQDGSGLWFGYGLLAPTKTHVEI Click to Show/Hide
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| 3D Structure | Click to Show 3D Structure of This Target | AlphaFold | ||||
| Drugs and Modes of Action | Top | |||||
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| Clinical Trial Drug(s) | [+] 3 Clinical Trial Drugs | + | ||||
| 1 | PMX-53 | Drug Info | Phase 2 | Atopic dermatitis | [4], [5] | |
| 2 | Rambazole | Drug Info | Phase 2 | Psoriasis vulgaris | [6] | |
| 3 | Nepadutant | Drug Info | Phase 1/2 | Postoperative ileus | [7], [8] | |
| Discontinued Drug(s) | [+] 12 Discontinued Drugs | + | ||||
| 1 | Saredutant | Drug Info | Discontinued in Phase 3 | Anxiety disorder | [9], [10] | |
| 2 | CS-003 | Drug Info | Discontinued in Phase 2 | Chronic obstructive pulmonary disease | [11] | |
| 3 | DNK-333 | Drug Info | Discontinued in Phase 2 | Irritable bowel syndrome | [11] | |
| 4 | FK-224 | Drug Info | Discontinued in Phase 2 | Asthma | [12], [13] | |
| 5 | SR 144190 | Drug Info | Discontinued in Phase 1 | Urinary incontinence | [15] | |
| 6 | UK-224671 | Drug Info | Discontinued in Phase 1 | Urinary incontinence | [16] | |
| 7 | AZD-5106 | Drug Info | Terminated | Urinary incontinence | [18] | |
| 8 | GR-159897 | Drug Info | Terminated | Anxiety disorder | [19], [20] | |
| 9 | MEN-10207 | Drug Info | Terminated | Pain | [21] | |
| 10 | MEN-10627 | Drug Info | Terminated | Asthma | [22], [23] | |
| 11 | UK-290795 | Drug Info | Terminated | Urinary incontinence | [24] | |
| 12 | ZD-7944 | Drug Info | Terminated | Asthma | [25] | |
| Preclinical Drug(s) | [+] 1 Preclinical Drugs | + | ||||
| 1 | SLV-332 | Drug Info | Preclinical | Irritable bowel syndrome | [17] | |
| Mode of Action | [+] 4 Modes of Action | + | ||||
| Inhibitor | [+] 6 Inhibitor drugs | + | ||||
| 1 | PMX-53 | Drug Info | [26] | |||
| 2 | L-732138 | Drug Info | [41] | |||
| 3 | 4-(4-butylpiperidin-1-yl)-1-o-tolylbutan-1-one | Drug Info | [46] | |||
| 4 | A-987306 | Drug Info | [47] | |||
| 5 | Hoo-Phe-Orn-Pro-hle-Pff-Phe-NH2 | Drug Info | [26] | |||
| 6 | WAY-207024 | Drug Info | [53] | |||
| Antagonist | [+] 16 Antagonist drugs | + | ||||
| 1 | Rambazole | Drug Info | [27] | |||
| 2 | Nepadutant | Drug Info | [8] | |||
| 3 | Saredutant | Drug Info | [28], [29], [30], [31] | |||
| 4 | CS-003 | Drug Info | [11] | |||
| 5 | SR 144190 | Drug Info | [36], [37] | |||
| 6 | UK-224671 | Drug Info | [38] | |||
| 7 | SLV-332 | Drug Info | [17] | |||
| 8 | AZD-5106 | Drug Info | [39] | |||
| 9 | UK-290795 | Drug Info | [44] | |||
| 10 | GR100679 | Drug Info | [48] | |||
| 11 | GR94800 | Drug Info | [49] | |||
| 12 | R396 | Drug Info | [51] | |||
| 13 | SCH 206272 | Drug Info | [52] | |||
| 14 | YM49598 | Drug Info | [54] | |||
| 15 | ZM 253270 | Drug Info | [55] | |||
| 16 | ZM-274773 | Drug Info | [56] | |||
| Modulator | [+] 6 Modulator drugs | + | ||||
| 1 | DNK-333 | Drug Info | [32] | |||
| 2 | FK-224 | Drug Info | [33], [34], [35] | |||
| 3 | GR-159897 | Drug Info | [40] | |||
| 4 | MEN-10207 | Drug Info | [42] | |||
| 5 | MEN-10627 | Drug Info | [43] | |||
| 6 | ZD-7944 | Drug Info | [45] | |||
| Agonist | [+] 1 Agonist drugs | + | ||||
| 1 | neurokinin A | Drug Info | [50] | |||
| 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 | 2 | Degree centrality | 2.15E-04 | Betweenness centrality | 3.20E-04 |
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| Closeness centrality | 1.66E-01 | Radiality | 1.26E+01 | Clustering coefficient | 0.00E+00 |
| Neighborhood connectivity | 3.50E+00 | Topological coefficient | 5.00E-01 | Eccentricity | 13 |
| 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 | |||||
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| 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 | Antagonist profile of ibodutant at the tachykinin NK2 receptor in guinea pig isolated bronchi. Eur J Pharmacol. 2013 Nov 15;720(1-3):180-5. | |||||
| REF 2 | 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: 2117). | |||||
| REF 3 | ClinicalTrials.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 4 | 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: 579). | |||||
| REF 5 | PMX-53 as a dual CD88 antagonist and an agonist for Mas-related gene 2 (MrgX2) in human mast cells. Mol Pharmacol. 2011 Jun;79(6):1005-13. | |||||
| REF 6 | Emerging drugs for psoriasis. Expert Opin Emerg Drugs. 2009 Mar;14(1):145-63. | |||||
| REF 7 | 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: 2123). | |||||
| REF 8 | Emerging drugs for postoperative ileus. Expert Opin Emerg Drugs. 2007 Nov;12(4):619-26. | |||||
| 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: 2111). | |||||
| REF 10 | Novel drugs and therapeutic targets for severe mood disorders. Neuropsychopharmacology. 2008 Aug;33(9):2080-92. | |||||
| 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: 2103). | |||||
| 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 800001455) | |||||
| REF 14 | Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800021516) | |||||
| REF 15 | Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800008589) | |||||
| REF 16 | Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800010850) | |||||
| REF 17 | Emerging drugs for irritable bowel syndrome. Expert Opin Emerg Drugs. 2006 May;11(2):293-313. | |||||
| REF 18 | Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800015341) | |||||
| REF 19 | 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: 2115). | |||||
| REF 20 | Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800003215) | |||||
| REF 21 | Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800003687) | |||||
| REF 22 | 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: 3901). | |||||
| REF 23 | Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800004991) | |||||
| REF 24 | Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800017162) | |||||
| REF 25 | Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800007349) | |||||
| REF 26 | Peptidomimetic C5a receptor antagonists with hydrophobic substitutions at the C-terminus: increased receptor specificity and in vivo activity. Bioorg Med Chem Lett. 2006 Oct 1;16(19):5088-92. | |||||
| REF 27 | Pharmacology 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 28 | Characterization of species-related differences in the pharmacology of tachykinin NK receptors 1, 2 and 3. Biochem Pharmacol. 2009 May 1;77(9):1522-30. | |||||
| REF 29 | Multifaceted approach to determine the antagonist molecular mechanism and interaction of ibodutant ([1-(2-phenyl-1R-[[1-(tetrahydropyran-4-ylmethyl... J Pharmacol Exp Ther. 2009 May;329(2):486-95. | |||||
| REF 30 | Occurrence and pharmacological characterization of four human tachykinin NK2 receptor variants. Biochem Pharmacol. 2008 Aug 15;76(4):476-81. | |||||
| REF 31 | Expression of rat NK-2 (neurokinin A) receptor in E. coli. Receptors Channels. 1994;2(4):295-302. | |||||
| REF 32 | Dual tachykinin NK1/NK2 antagonist DNK333 inhibits neurokinin A-induced bronchoconstriction in asthma patients. Eur Respir J. 2004 Jan;23(1):76-81. | |||||
| REF 33 | Effects of FK224, a novel compound NK1 and NK2 receptor antagonist, on airway constriction and airway edema induced by neurokinins and sensory nerv... J Pharmacol Exp Ther. 1992 Jul;262(1):403-8. | |||||
| REF 34 | FK 224, a novel cyclopeptide substance P antagonist with NK1 and NK2 receptor selectivity. J Pharmacol Exp Ther. 1992 Jul;262(1):398-402. | |||||
| REF 35 | [Discovery and pharmacological properties of selective neurokinin-receptor antagonists, FK224 and FK888].Nihon Yakurigaku Zasshi.1995 Sep;106(3):193-204. | |||||
| REF 36 | Pharmacologic evaluation of neurokinin-2 receptor antagonists in the guinea pig respiratory tract. Am J Vet Res. 2004 Jul;65(7):984-91. | |||||
| REF 37 | Antagonists at the neurokinin receptors--recent patent literature. IDrugs. 2003 Aug;6(8):758-72. | |||||
| REF 38 | Pharmacokinetics and metabolism of a sulphamide NK2 antagonist in rat, dog and human. Xenobiotica. 2000 Jun;30(6):627-42. | |||||
| REF 39 | Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800015341) | |||||
| REF 40 | GR159897, a potent non-peptide antagonist at tachykinin NK2 receptors. Eur J Pharmacol. 1995 Jan 16;272(2-3):241-8. | |||||
| REF 41 | Biological and conformational evaluation of bifunctional compounds for opioid receptor agonists and neurokinin 1 receptor antagonists possessing tw... J Med Chem. 2010 Aug 12;53(15):5491-501. | |||||
| REF 42 | Role of D-tryptophan for affinity of MEN 10207 tachykinin antagonist at NK2 receptors. Peptides. 1991 Sep-Oct;12(5):1015-8. | |||||
| REF 43 | MEN 10,627, a novel polycyclic peptide antagonist of tachykinin NK2 receptors. J Pharmacol Exp Ther. 1994 Dec;271(3):1489-500. | |||||
| REF 44 | Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800017162) | |||||
| REF 45 | Discovery of novel, orally active dual NK1/NK2 antagonists. Bioorg Med Chem Lett. 2001 Oct 22;11(20):2769-73. | |||||
| REF 46 | 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 rec... J Med Chem. 2010 Sep 9;53(17):6386-97. | |||||
| REF 47 | 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... J Med Chem. 2008 Nov 27;51(22):7094-8. | |||||
| REF 48 | Characterisation, CNS distribution and function of NK2 receptors studied using potent NK2 receptor antagonists. Regul Pept. 1993 Jul 2;46(1-2):9-19. | |||||
| REF 49 | Synthesis and characterization of selective fluorescent ligands for the neurokinin NK2 receptor. J Med Chem. 1994 Jun 24;37(13):1991-5. | |||||
| REF 50 | Structure-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. | |||||
| REF 51 | Characterization 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 52 | 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. | |||||
| REF 53 | 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 ... J Med Chem. 2009 Apr 9;52(7):2148-52. | |||||
| REF 54 | Effect 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 55 | Pharmacological 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 56 | Tachykinin NK2 receptor antagonists. A patent review (2006 - 2010). Expert Opin Ther Pat. 2012 Jan;22(1):57-77. | |||||
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