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Imidazole-derived agonists for the neurotensin 1 receptor.

ABSTRACT: A scaffold-hop program seeking full agonists of the neurotensin-1 (NTR1) receptor identified the probe molecule ML301 (1) and associated analogs, including its naphthyl analog (14) which exhibited similar properties. Compound 1 showed full agonist behavior (79-93%) with an EC50 of 2.0-4.1?M against NTR1. Compound 1 also showed good activity in a Ca mobilization FLIPR assay (93% efficacy at 298nM), consistent with it functioning via the Gq coupled pathway, and good selectivity relative to NTR2 and GPR35. In further profiling, 1 showed low potential for promiscuity and good overall pharmacological data. This report describes the discovery, synthesis, and SAR of 1 and associated analogs. Initial in vitro pharmacologic characterization is also presented.

SUBMITTER: Hershberger PM

PROVIDER: S-EPMC3898338 | biostudies-literature | 2014 Jan

REPOSITORIES: biostudies-literature

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Imidazole-derived agonists for the neurotensin 1 receptor.

Hershberger Paul M PM Hedrick Michael P MP Peddibhotla Satyamaheshwar S Mangravita-Novo Arianna A Gosalia Palak P Li Yujie Y Gray Wilson W Vicchiarelli Michael M Smith Layton H LH Chung Thomas D Y TD Thomas James B JB Caron Marc G MG Pinkerton Anthony B AB Barak Lawrence S LS Roth Gregory P GP

Bioorganic & medicinal chemistry letters 20131121 1

A scaffold-hop program seeking full agonists of the neurotensin-1 (NTR1) receptor identified the probe molecule ML301 (1) and associated analogs, including its naphthyl analog (14) which exhibited similar properties. Compound 1 showed full agonist behavior (79-93%) with an EC50 of 2.0-4.1μM against NTR1. Compound 1 also showed good activity in a Ca mobilization FLIPR assay (93% efficacy at 298nM), consistent with it functioning via the Gq coupled pathway, and good selectivity relative to NTR2 an ...[more]

PMID: 24332089

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