Target Information
| Target General Information | Top | |||||
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| Target ID |
T02728
(Former ID: TTDC00144)
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| Target Name |
Neurotensin receptor type 1 (NTSR1)
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| Synonyms |
NTSR1; NTRH; NTR1; NTR subtype 1; NT-R1; NT-R-1; High-affinity levocabastine-insensitive neurotensin receptor
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| Gene Name |
NTSR1
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| Target Type |
Clinical trial target
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[1] | ||||
| Disease | [+] 1 Target-related Diseases | + | ||||
| 1 | Indeterminate colitis [ICD-11: DD72] | |||||
| Function |
G-protein coupled receptor for the tridecapeptide neurotensin (NTS). Signaling is effected via G proteins that activate a phosphatidylinositol-calcium second messenger system. Signaling leads to the activation of downstream MAP kinases and protects cells against apoptosis.
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| BioChemical Class |
GPCR rhodopsin
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| UniProt ID | ||||||
| Sequence |
MRLNSSAPGTPGTPAADPFQRAQAGLEEALLAPGFGNASGNASERVLAAPSSELDVNTDI
YSKVLVTAVYLALFVVGTVGNTVTAFTLARKKSLQSLQSTVHYHLGSLALSDLLTLLLAM PVELYNFIWVHHPWAFGDAGCRGYYFLRDACTYATALNVASLSVERYLAICHPFKAKTLM SRSRTKKFISAIWLASALLAVPMLFTMGEQNRSADGQHAGGLVCTPTIHTATVKVVIQVN TFMSFIFPMVVISVLNTIIANKLTVMVRQAAEQGQVCTVGGEHSTFSMAIEPGRVQALRH GVRVLRAVVIAFVVCWLPYHVRRLMFCYISDEQWTPFLYDFYHYFYMVTNALFYVSSTIN PILYNLVSANFRHIFLATLACLCPVWRRRRKRPAFSRKADSVSSNHTLSSNATRETLY Click to Show/Hide
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| 3D Structure | Click to Show 3D Structure of This Target | PDB | ||||
| Drugs and Modes of Action | Top | |||||
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| Clinical Trial Drug(s) | [+] 1 Clinical Trial Drugs | + | ||||
| 1 | Meclinertant | Drug Info | Phase 2/3 | Inflammatory bowel disease | [2], [3] | |
| Discontinued Drug(s) | [+] 2 Discontinued Drugs | + | ||||
| 1 | ABS-212 | Drug Info | Terminated | Pain | [4], [5] | |
| 2 | CGX-1160 | Drug Info | Terminated | Acute or chronic pain | [6], [7] | |
| Mode of Action | [+] 4 Modes of Action | + | ||||
| Antagonist | [+] 4 Antagonist drugs | + | ||||
| 1 | Meclinertant | Drug Info | [1], [8], [9] | |||
| 2 | SR142948A | Drug Info | [21] | |||
| 3 | SR48527 | Drug Info | [22] | |||
| 4 | [3H]meclinertant | Drug Info | [22] | |||
| Agonist | [+] 4 Agonist drugs | + | ||||
| 1 | ABS-212 | Drug Info | [10] | |||
| 2 | CGX-1160 | Drug Info | [11], [12] | |||
| 3 | JMV449 | Drug Info | [17] | |||
| 4 | JMV458 | Drug Info | [18] | |||
| Inhibitor | [+] 9 Inhibitor drugs | + | ||||
| 1 | 4-(4-butylpiperidin-1-yl)-1-o-tolylbutan-1-one | Drug Info | [13] | |||
| 2 | Demotensin 1 | Drug Info | [14] | |||
| 3 | Demotensin 3 | Drug Info | [14] | |||
| 4 | H-Arg-Arg-Pro-Tyr-Ile-Aac-OH | Drug Info | [15] | |||
| 5 | H-Arg-Arg-Pro-Tyr-Ile-N-Me-Leu-OH | Drug Info | [15] | |||
| 6 | H-Arg-Arg-Pro-Tyr-N-Me-Ile-Leu-OH | Drug Info | [15] | |||
| 7 | H-Arg-N-Me-Arg-Pro-Tyr-Ile-Leu-OH | Drug Info | [15] | |||
| 8 | NEUROTENSIN | Drug Info | [19] | |||
| 9 | Neurotensin(8-13) | Drug Info | [20] | |||
| Modulator | [+] 1 Modulator drugs | + | ||||
| 1 | HBN-2 | Drug Info | [16] | |||
| Cell-based Target Expression Variations | Top | |||||
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| Cell-based Target Expression Variations | ||||||
| Drug Binding Sites of Target | Top | |||||
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| Ligand Name: [(2r)-2-Octanoyloxy-3-[oxidanyl-[(1r,2r,3s,4r,5r,6s)-2,3,6-Tris(Oxidanyl)-4,5-Diphosphonooxy-Cyclohexyl]oxy-Phosphoryl]oxy-Propyl] Octanoate | Ligand Info | |||||
| Structure Description | neurotensin receptor and arrestin2 complex | PDB:6UP7 | ||||
| Method | Electron microscopy | Resolution | 4.20 Å | Mutation | Yes | [23] |
| PDB Sequence |
PSSELDVNTD
59 IYSKVLVTAV69 YLALFVVGTV79 GNTVTAFTLA89 RKKSLQSLQS99 TVHYHLGSLA 109 LSDLLTLLLA119 MPVELYNFIW129 VHHPWAFGDA139 GCRGYYFLRD149 ACTYATALNV 159 ASLSVERYLA169 ICHPFKAKTL179 MSRSRTKKFI189 SAIWLASALL199 AVPMLFTMGE 209 QNRSADGQHA219 GGLVCTPTIH229 TATVKVVIQV239 NTFMSFIFPM249 VVISVLNTII 259 ANKLTVMVRQ269 AAEQFSMAIE291 PGRVQALRHG301 VRVLRAVVIA311 FVVCWLPYHV 321 RRLMFCYISD331 EQWTPFLYDF341 YHYFYMVTNA351 LFYVSSTINP361 ILYNLVSANF 371 RHIFLATLAC381 LC
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| Click to View More Binding Site Information of This Target with Different Ligands | ||||||
| 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 | 4.11E-05 |
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| Closeness centrality | 1.83E-01 | Radiality | 1.31E+01 | Clustering coefficient | 0.00E+00 |
| Neighborhood connectivity | 1.40E+01 | Topological coefficient | 5.00E-01 | Eccentricity | 12 |
| 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 Affiliated Biological Pathways | Top | |||||
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| KEGG Pathway | [+] 2 KEGG Pathways | + | ||||
| 1 | Calcium signaling pathway | |||||
| 2 | Neuroactive ligand-receptor interaction | |||||
| Reactome | [+] 2 Reactome Pathways | + | ||||
| 1 | Peptide ligand-binding receptors | |||||
| 2 | G alpha (q) signalling events | |||||
| WikiPathways | [+] 6 WikiPathways | + | ||||
| 1 | GPCRs, Class A Rhodopsin-like | |||||
| 2 | Gastrin-CREB signalling pathway via PKC and MAPK | |||||
| 3 | Peptide GPCRs | |||||
| 4 | GPCR ligand binding | |||||
| 5 | GPCR downstream signaling | |||||
| 6 | GPCRs, Other | |||||
| Target-Related Models and Studies | Top | |||||
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| Target Validation | ||||||
| References | Top | |||||
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| REF 1 | Neurotensin inversely modulates maternal aggression. Neuroscience. 2009 Feb 18;158(4):1215-23. | |||||
| 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: 1582). | |||||
| REF 3 | ClinicalTrials.gov (NCT00290953) Evaluation of the Overall Survival of Meclinertant Versus Placebo After a First Line Chemotherapy With Cisplatin + Etoposide. 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: 5307). | |||||
| REF 5 | Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800026502) | |||||
| REF 6 | 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: 1575). | |||||
| REF 7 | Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800012898) | |||||
| REF 8 | Stimulation by neurotensin of dopamine and 5-hydroxytryptamine (5-HT) release from rat prefrontal cortex: possible role of NTR1 receptors in neurop... Neurochem Int. 2008 Dec;53(6-8):355-61. | |||||
| REF 9 | High-affinity neurotensin receptor is involved in phosphoinositide turnover increase by inhibition of sodium pump in neonatal rat brain. Neurochem Res. 2008 Nov;33(11):2206-13. | |||||
| REF 10 | Identification and functional characterization of a stable, centrally active derivative of the neurotensin (8-13) fragment as a potential first-in-class analgesic. J Med Chem. 2010 Jun 24;53(12):4623-32. | |||||
| REF 11 | Clinical status of anti-cancer agents derived from marine sources. Anticancer Agents Med Chem. 2008 Aug;8(6):603-17. | |||||
| REF 12 | The pharmacokinetics of the conopeptide contulakin-G (CGX-1160) after intrathecal administration: an analysis of data from studies in beagles. Anesth Analg. 2007 Jun;104(6):1514-20, table of contents. | |||||
| REF 13 | 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 14 | Toward stable N4-modified neurotensins for NTS1-receptor-targeted tumor imaging with 99mTc. J Med Chem. 2006 Jul 27;49(15):4767-76. | |||||
| REF 15 | Novel insights into GPCR-peptide interactions: mutations in extracellular loop 1, ligand backbone methylations and molecular modeling of neurotensi... Bioorg Med Chem. 2008 Oct 15;16(20):9359-68. | |||||
| REF 16 | 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: 309). | |||||
| REF 17 | Differential involvement of intracellular domains of the rat NTS1 neurotensin receptor in coupling to G proteins: a molecular basis for agonist-directed trafficking of receptor stimulus. Mol Pharmacol. 2003 Aug;64(2):421-9. | |||||
| REF 18 | Agonism, inverse agonism, and neutral antagonism at the constitutively active human neurotensin receptor 2. Mol Pharmacol. 2001 Dec;60(6):1392-8. | |||||
| REF 19 | Identification of a potent, selective, and orally active leukotriene a4 hydrolase inhibitor with anti-inflammatory activity. J Med Chem. 2008 Jul 24;51(14):4150-69. | |||||
| REF 20 | Comparison of N-terminal modifications on neurotensin(8-13) analogues correlates peptide stability but not binding affinity with in vivo efficacy. J Med Chem. 2009 Apr 9;52(7):1803-13. | |||||
| REF 21 | Biochemical and pharmacological activities of SR 142948A, a new potent neurotensin receptor antagonist. J Pharmacol Exp Ther. 1997 Feb;280(2):802-12. | |||||
| REF 22 | [3H]SR 48692, the first nonpeptide neurotensin antagonist radioligand: characterization of binding properties and evidence for distinct agonist and antagonist binding domains on the rat neurotensin receptor. Mol Pharmacol. 1995 May;47(5):1050-6. | |||||
| REF 23 | Structure of the neurotensin receptor 1 in complex with beta-arrestin 1. Nature. 2020 Mar;579(7798):303-308. | |||||
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