Dataset Information

Identification and SAR of Glycine Benzamides as Potent Agonists for the GPR139 Receptor.

ABSTRACT: A focused high throughput screening for GPR139 was completed for a select 100K compounds, and new agonist leads were identified. Subsequent analysis and structure-activity relationship studies identified (S)-3-chloro-N-(2-oxo-2-((1-phenylethyl)amino)ethyl)benzamide 7c as a potent and selective agonist of hGPR139 with an EC50 = 16 nM. The compound was found to cross the blood-brain barrier and have good drug-like properties amenable for oral dosing in rat.

SUBMITTER: Dvorak CA

PROVIDER: S-EPMC4569879 | biostudies-literature | 2015 Sep

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Identification and SAR of Glycine Benzamides as Potent Agonists for the GPR139 Receptor.

Dvorak Curt A CA Coate Heather H Nepomuceno Diane D Wennerholm Michelle M Kuei Chester C Lord Brian B Woody David D Bonaventure Pascal P Liu Changlu C Lovenberg Timothy T Carruthers Nicholas I NI

ACS medicinal chemistry letters 20150720 9

A focused high throughput screening for GPR139 was completed for a select 100K compounds, and new agonist leads were identified. Subsequent analysis and structure-activity relationship studies identified (S)-3-chloro-N-(2-oxo-2-((1-phenylethyl)amino)ethyl)benzamide 7c as a potent and selective agonist of hGPR139 with an EC50 = 16 nM. The compound was found to cross the blood-brain barrier and have good drug-like properties amenable for oral dosing in rat. ...[more]

PMID: 26396690

Similar Datasets

Project description:Natural products are an abundant source of potential drugs, and their diversity makes them a rich and viable prospective source of bioactive cannabinoid ligands. Cannabinoid receptor 1 (CB1) antagonists are clinically established and well documented as potential therapeutics for treating obesity, obesity-related cardiometabolic disorders, pain, and drug/substance abuse, but their associated CNS-mediated adverse effects hinder the development of potential new drugs and no such drug is currently on the market. This limitation amplifies the need for new agents with reduced or no CNS-mediated side effects. We are interested in the discovery of new natural product chemotypes as CB1 antagonists, which may serve as good starting points for further optimization towards the development of CB1 therapeutics. In search of new chemotypes as CB1 antagonists, we screened the in silico purchasable natural products subset of the ZINC12 database against our reported CB1 receptor model using the structure-based virtual screening (SBVS) approach. A total of 18 out of 192 top-scoring virtual hits, selected based on structural diversity and key protein⁻ligand interactions, were purchased and subjected to in vitro screening in competitive radioligand binding assays. The in vitro screening yielded seven compounds exhibiting >50% displacement at 10 μM concentration, and further binding affinity (Ki and IC50) and functional data revealed compound 16 as a potent and selective CB1 inverse agonist (Ki = 121 nM and EC50 = 128 nM) while three other compounds-2, 12, and 18-were potent but nonselective CB1 ligands with low micromolar binding affinity (Ki). In order to explore the structure⁻activity relationship for compound 16, we further purchased compounds with >80% similarity to compound 16, screened them for CB1 and CB2 activities, and found two potent compounds with sub-micromolar activities. Most importantly, these bioactive compounds represent structurally new natural product chemotypes in the area of cannabinoid research and could be considered for further structural optimization as CB1 ligands.

Dataset Information

Identification and SAR of Glycine Benzamides as Potent Agonists for the GPR139 Receptor.

Publications

Identification and SAR of Glycine Benzamides as Potent Agonists for the GPR139 Receptor.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets