• Journal Article

Imidazole-derived agonists for the neurotensin 1 receptor


Hershberger, P. M., Hedrick, M. P., Peddibhotla, S., Mangravita-Novo, A., Gosalia, P., Li, Y., ... Roth, G. P. (2014). Imidazole-derived agonists for the neurotensin 1 receptor. Bioorganic and Medicinal Chemistry Letters, 24(1), 262-267. DOI: 10.1016/j.bmcl.2013.11.026


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 2.0-4.1muM 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