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Discovery of ML314, a Brain Penetrant Non-Peptidic β-Arrestin Biased Agonist of the Neurotensin NTR1 Receptor.ML314的发现，一种可穿透血脑屏障的神经降压素NTR1受体的非肽类β-抑制蛋白偏向性激动剂。
ACS Med Chem Lett. 2013 Jul 20;4(9):846-851. doi: 10.1021/ml400176n.
2
Imidazole-derived agonists for the neurotensin 1 receptor.用于神经降压素 1 受体的咪唑衍生激动剂。
Bioorg Med Chem Lett. 2014 Jan 1;24(1):262-7. doi: 10.1016/j.bmcl.2013.11.026. Epub 2013 Nov 21.
3
Acute, but not repeated, administration of the neurotensin NTS1 receptor agonist PD149163 decreases conditioned footshock-induced ultrasonic vocalizations in rats.急性而非重复给予神经降压素 NTS1 受体激动剂 PD149163 可减少大鼠条件性足底电击诱导的超声发声。
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The identification of nonpeptide neurotensin receptor partial agonists from the potent antagonist SR48692 using a calcium mobilization assay.使用钙动员测定法从强效拮抗剂SR48692中鉴定非肽神经降压素受体部分激动剂。
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神经降压素受体1（NTSR1）吲哚完全激动剂的发现。

The discovery of indole full agonists of the neurotensin receptor 1 (NTSR1).

作者信息

Di Fruscia Paolo, He Yuanjun, Koenig Marcel, Tabrizifard Sahba, Nieto Ainhoa, McDonald Patricia H, Kamenecka Theodore M

机构信息

Department of Molecular Therapeutics and Translational Research Institute, The Scripps Research Institute, Scripps Florida, 130 Scripps Way #A2A, Jupiter, FL 33458, USA.

Department of Molecular Therapeutics and Translational Research Institute, The Scripps Research Institute, Scripps Florida, 130 Scripps Way #A2A, Jupiter, FL 33458, USA.

出版信息

Bioorg Med Chem Lett. 2014 Aug 15;24(16):3974-8. doi: 10.1016/j.bmcl.2014.06.033. Epub 2014 Jun 20.

DOI:10.1016/j.bmcl.2014.06.033
PMID:24997685
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC4130903/
Abstract

Neurotensin (NT) is an endogenous tridecapeptide found in the central nervous system (CNS) and in peripheral tissues. Neurotensin exerts a wide range of physiological effects and it has been found to play a critical role in a number of human diseases, such as schizophrenia, Parkinson's disease and drug addiction. The discovery of small-molecule non-peptide neurotensin receptor (NTSR) modulators would represent an important breakthrough as such compounds could be used as pharmacological tools, to further decipher the cellular functions of neurotensin, and potentially as therapeutic agents to treat human disease. Herein, we report the identification of non-peptide low-micromolar neurotensin receptor 1 (NTSR1) full agonists, discovered through structural optimization of the known NTSR1 partial agonist 1. In vitro cellular screenings, based on an intracellular Ca(2+) mobilization assay, revealed our best hit molecule 8 (SR-12062) to have an EC50 of 2 μM at NTSR1 with full agonist behaviour (Emax=100%), showing a higher efficacy and ∼90-fold potency improvement compared to parent compound 1 (EC50=178 μM; Emax=17%).

摘要

神经降压素（NT）是一种内源性十三肽，存在于中枢神经系统（CNS）和外周组织中。神经降压素具有广泛的生理作用，并且已发现在多种人类疾病中起关键作用，如精神分裂症、帕金森病和药物成瘾。发现小分子非肽神经降压素受体（NTSR）调节剂将是一项重要突破，因为这类化合物可作为药理学工具，进一步阐明神经降压素的细胞功能，并有可能作为治疗人类疾病的治疗药物。在此，我们报告通过对已知的NTSR1部分激动剂1进行结构优化，鉴定出非肽低微摩尔神经降压素受体1（NTSR1）完全激动剂。基于细胞内Ca(2+)动员试验的体外细胞筛选显示，我们最有效的分子8（SR-12062）在NTSR1上的EC50为2 μM，具有完全激动剂行为（Emax=100%），与母体化合物1相比，显示出更高的效力和约90倍的效能提高（EC50=178 μM；Emax=17%）。