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.

Full Text

Duke Authors

Cited Authors

  • 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

Published Date

  • January 1, 2014

Published In

Volume / Issue

  • 24 / 1

Start / End Page

  • 262 - 267

PubMed ID

  • 24332089

Pubmed Central ID

  • PMC3898338

Electronic International Standard Serial Number (EISSN)

  • 1464-3405

Digital Object Identifier (DOI)

  • 10.1016/j.bmcl.2013.11.026


  • eng

Conference Location

  • England