Target Validation Information
Target ID T02728
Target Name Neurotensin receptor type 1
Target Type
Clinical Trial
Drug Potency against Target CGX-1160 Drug Info IC50 = 500 nM [552382]
H-Arg-Arg-Pro-Tyr-N-Me-Ile-Leu-OH Drug Info Ki = 160 nM [529709]
H-Arg-Arg-Pro-Tyr-Ile-Aac-OH Drug Info Ki = 2.4 nM [529709]
H-Arg-Arg-Pro-Tyr-Ile-N-Me-Leu-OH Drug Info Ki = 190 nM [529709]
4-(4-butylpiperidin-1-yl)-1-o-tolylbutan-1-one Drug Info Ki < 1000 nM [531079]
Demotensin 3 Drug Info IC50 = 1.5 nM [528326]
Demotensin 1 Drug Info IC50 = 0.32 nM [528326]
Demotensin 2 Drug Info IC50 = 0.41 nM [528326]
Neurotensin(8-13) Drug Info Ki = 0.14 nM [530025]
NEUROTENSIN Drug Info IC50 = 1.4 nM [529569]
Meclinertant Drug Info IC50 = 0.99 nM [530025]
Demotensin 4 Drug Info IC50 = 0.85 nM [528326]
H-Arg-N-Me-Arg-Pro-Tyr-Ile-Leu-OH Drug Info Ki = 0.51 nM [529709]
Action against Disease Model Meclinertant SR48692 (a non-peptide NT receptor antagonist) bound with high affinity (IC(50) = 20 nM) to NCI-H209 cells. Also, NT and SR48692 inhibited specific (125)I-NT binding with high affinity (IC(50) values of 2 and 200 nM). SR48692 (5 microM) antagonized the ability of NT (10 nM) to cause elevated cytosolic Ca2+ in Fura-2 AM loaded NCI-H209 cells. SR48692 antagonized the ability of NT to cause elevation of c-fos mRNA in these cells. Using a MTT proliferation assay, SR48692 inhibited NCI-H209 and H345 proliferation in a concentration-dependent manner. Using a clonogenic assay, 1 microM SR48692, reduced NCI-H209 colony n uMber. Also, SR48692 (0.4 mg/kg per day) inhibited NCI-H209 xenograft proliferation in nude mice. These results suggest that SR48692 is a NT(1) receptor antagonist which inhibits SCLC growth. [552243] Drug Info
The Effect of Target Knockout, Knockdown or Genetic Variations Much evidence suggests that targeting the neurotensin (NT) system may provide a novel and promising treatment for schizophrenia. Our recent work shows that: NTS1 knockout (NTS1(-/-)) mice may provide a potential animal model for studying schizophrenia by investigating the effect of deletion NTS1 receptor on amphetamine-induced hyperactivity and neurochemical changes. The data indicate a hyper-dopaminergic state similar to the excessive striatal DA activity reported in schizophrenia. The present study was done to determine if NTS1(-/-) mice also have similar changes in behavior, in prefrontal neurotransmitters, and in protein expression, as observed in wild type (WT) mice treated with the psychotomimetic phencylclidine (PCP), an animal model for schizophrenia. Our results showed many similarities between untreated NTS1(-/-) mice and WT mice chronically treated with PCP (as compared with untreated WT mice): 1) lower PCP-induced locomotor activity; 2) similar avolition-like behavior in forced-swim test and tail suspension test; 3) lower prefrontal glutamate levels; 4) less PCP-induced dopamine release in medial prefrontal cortex (mPFC); and 5) down-regulation ofmRNA and protein for DA D(1), DA D(2), and NMDAR2A in mPFC. Therefore, these data strengthen the hypothesis that the NTS1(-/-) mouse is an animal model of schizophrenia, particularly for the dysfunction of the prefrontal cortex. In addition, after chronic PCP administration, the DA D(1) receptor was up-regulated in NTS1(-/-) mice, results which suggest a possible interaction of NTS1/DA D(1) in mPFC contributing to chronic PCP-induced schizophrenia-like signs [552243]
References
Ref 552243SR48692 is a neurotensin receptor antagonist which inhibits the growth of small cell lung cancer cells. Peptides. 2001 Jan;22(1):109-15.
Ref 552382Therapeutic potential of venom peptides. Nat Rev Drug Discov. 2003 Oct;2(10):790-802.
Ref 529709Bioorg Med Chem. 2008 Oct 15;16(20):9359-68. Epub 2008 Aug 27.Novel insights into GPCR-peptide interactions: mutations in extracellular loop 1, ligand backbone methylations and molecular modeling ofneurotensin receptor 1.
Ref 529709Bioorg Med Chem. 2008 Oct 15;16(20):9359-68. Epub 2008 Aug 27.Novel insights into GPCR-peptide interactions: mutations in extracellular loop 1, ligand backbone methylations and molecular modeling ofneurotensin receptor 1.
Ref 529709Bioorg Med Chem. 2008 Oct 15;16(20):9359-68. Epub 2008 Aug 27.Novel insights into GPCR-peptide interactions: mutations in extracellular loop 1, ligand backbone methylations and molecular modeling ofneurotensin receptor 1.
Ref 531079J 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.
Ref 528326J Med Chem. 2006 Jul 27;49(15):4767-76.Toward stable N4-modified neurotensins for NTS1-receptor-targeted tumor imaging with 99mTc.
Ref 528326J Med Chem. 2006 Jul 27;49(15):4767-76.Toward stable N4-modified neurotensins for NTS1-receptor-targeted tumor imaging with 99mTc.
Ref 528326J Med Chem. 2006 Jul 27;49(15):4767-76.Toward stable N4-modified neurotensins for NTS1-receptor-targeted tumor imaging with 99mTc.
Ref 530025J Med Chem. 2009 Apr 9;52(7):1803-13.Comparison of N-terminal modifications on neurotensin(8-13) analogues correlates peptide stability but not binding affinity with in vivo efficacy.
Ref 529569J Med Chem. 2008 Jul 24;51(14):4150-69. Epub 2008 Jun 28.Identification of a potent, selective, and orally active leukotriene a4 hydrolase inhibitor with anti-inflammatory activity.
Ref 530025J Med Chem. 2009 Apr 9;52(7):1803-13.Comparison of N-terminal modifications on neurotensin(8-13) analogues correlates peptide stability but not binding affinity with in vivo efficacy.
Ref 528326J Med Chem. 2006 Jul 27;49(15):4767-76.Toward stable N4-modified neurotensins for NTS1-receptor-targeted tumor imaging with 99mTc.
Ref 529709Bioorg Med Chem. 2008 Oct 15;16(20):9359-68. Epub 2008 Aug 27.Novel insights into GPCR-peptide interactions: mutations in extracellular loop 1, ligand backbone methylations and molecular modeling ofneurotensin receptor 1.

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