Imidazole-derived agonists for the neurotensin 1 receptor.
Journal Article (Journal Article)
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 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.
- Hershberger, PM; Hedrick, MP; Peddibhotla, S; Mangravita-Novo, A; Gosalia, P; Li, Y; Gray, W; Vicchiarelli, M; Smith, LH; Chung, TDY; Thomas, JB; Caron, MG; Pinkerton, AB; Barak, LS; Roth, GP
- January 1, 2014
Volume / Issue
- 24 / 1
Start / End Page
- 262 - 267
Pubmed Central ID
Electronic International Standard Serial Number (EISSN)
Digital Object Identifier (DOI)