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

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS

卷:24

Article

Kamenecka, Theodore M.¹ 

[1] Scripps Florida, Scripps Res Inst, Dept Mol Therapeut, Jupiter, FL 33458 USA

关键词: SR-12062;    Neurotensin;    Neurotensin receptors;    Neurotensin agonists;    Indole agonists;   

DOI  :  10.1016/j.bmcl.2014.06.033

来源: Elsevier

【 摘 要 】

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 Ca2+ mobilization assay, revealed our best hit molecule 8 (SR-12062) to have an EC50 of 2 mu M at NTSR1 with full agonist behaviour (E-max = 100%), showing a higher efficacy and similar to 90-fold potency improvement compared to parent compound 1 (EC50 = 178 mu M; E-max = 17%). (C) 2014 Elsevier Ltd. All rights reserved.

【 授权许可】

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