title: 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 2.0-4.1μM 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.
authors: Conrad Prebys Center for Chemical Genomics at Sanford-Burnham Medical Research Institute, Orlando, FL 32827, USA. Electronic address: phershberger@sanfordburnham.org.
authors: Paul M
authors: PM
authors: Hershberger
authors: Conrad Prebys Center for Chemical Genomics at Sanford-Burnham Medical Research Institute, La Jolla, CA 92037, USA.
authors: Michael P
authors: MP
authors: Hedrick
authors: Conrad Prebys Center for Chemical Genomics at Sanford-Burnham Medical Research Institute, Orlando, FL 32827, USA.
authors: Satyamaheshwar
authors: S
authors: Peddibhotla
authors: Conrad Prebys Center for Chemical Genomics at Sanford-Burnham Medical Research Institute, Orlando, FL 32827, USA.
authors: Arianna
authors: A
authors: Mangravita-Novo
authors: Conrad Prebys Center for Chemical Genomics at Sanford-Burnham Medical Research Institute, La Jolla, CA 92037, USA.
authors: Palak
authors: P
authors: Gosalia
authors: Conrad Prebys Center for Chemical Genomics at Sanford-Burnham Medical Research Institute, La Jolla, CA 92037, USA.
authors: Yujie
authors: Y
authors: Li
authors: Conrad Prebys Center for Chemical Genomics at Sanford-Burnham Medical Research Institute, La Jolla, CA 92037, USA.
authors: Wilson
authors: W
authors: Gray
authors: Conrad Prebys Center for Chemical Genomics at Sanford-Burnham Medical Research Institute, Orlando, FL 32827, USA.
authors: Michael
authors: M
authors: Vicchiarelli
authors: Conrad Prebys Center for Chemical Genomics at Sanford-Burnham Medical Research Institute, Orlando, FL 32827, USA.
authors: Layton H
authors: LH
authors: Smith
authors: Conrad Prebys Center for Chemical Genomics at Sanford-Burnham Medical Research Institute, La Jolla, CA 92037, USA.
authors: Thomas D Y
authors: TD
authors: Chung
authors: RTI International, 3040 E Cornwallis Road, Durham, NC 27709, USA.
authors: James B
authors: JB
authors: Thomas
authors: Duke University Medical Center, Durham, NC 27710, USA.
authors: Marc G
authors: MG
authors: Caron
authors: Conrad Prebys Center for Chemical Genomics at Sanford-Burnham Medical Research Institute, La Jolla, CA 92037, USA.
authors: Anthony B
authors: AB
authors: Pinkerton
authors: Duke University Medical Center, Durham, NC 27710, USA.
authors: Lawrence S
authors: LS
authors: Barak
authors: Conrad Prebys Center for Chemical Genomics at Sanford-Burnham Medical Research Institute, Orlando, FL 32827, USA.
authors: Gregory P
authors: GP
authors: Roth
mesh_terms: D000818:Animals; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007093:Imidazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D051379:Mice; D015394:Molecular Structure; D018028:Receptors, Neurotensin / Q000819:agonists*; D013329:Structure-Activity Relationship
chemical_list: D007093:Imidazoles; D018028:Receptors, Neurotensin; C114036:neurotensin type 1 receptor; C029899:imidazole
keywords: Agonist; Imidazole; Methamphetamine; Neurotensin 1