Improvement of the Metabolic Stability of GPR88 Agonist RTI-13951-33: Design, Synthesis, and Biological Evaluation

GPR88 is an orphan G protein-coupled receptor mainly expressed in the brain, whose endogenous ligand has not yet been identified. To elucidate GPR88 functions, our group has developed RTI-13951-33 (1b) as the first in vivo active GPR88 agonist, but its poor metabolic stability and moderate brain per...

Full description

Saved in:
Bibliographic Details
Published in:Journal of medicinal chemistry 2023-02, Vol.66 (4), p.2964-2978
Main Authors: Rahman, Md Toufiqur, Decker, Ann M., Ben Hamida, Sami, Perrey, David A., Chaminda Lakmal, Hetti Handi, Maitra, Rangan, Darcq, Emmanuel, Kieffer, Brigitte L., Jin, Chunyang
Format: Article
Language:English
Subjects:
Alcohol Drinking - drug therapy
Animals
Brain - metabolism
Drug Design
Drug Stability
Life Sciences
Mice
Receptors, G-Protein-Coupled - agonists
Toxicology
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:GPR88 is an orphan G protein-coupled receptor mainly expressed in the brain, whose endogenous ligand has not yet been identified. To elucidate GPR88 functions, our group has developed RTI-13951-33 (1b) as the first in vivo active GPR88 agonist, but its poor metabolic stability and moderate brain permeability remain to be further optimized. Here, we report the design, synthesis, and pharmacological characterization of a new series of RTI-13951-33 analogues with the aim of improving pharmacokinetic properties. As a result, we identified a highly potent GPR88 agonist RTI-122 (30a) (cAMP EC50 = 11 nM) with good metabolic stability (half-life of 5.8 h) and brain permeability (brain/plasma ratio of >1) in mice. Notably, RTI-122 was more effective than RTI-13951-33 in attenuating the binge-like alcohol drinking behavior in the drinking-in-the-dark paradigm. Collectively, our findings suggest that RTI-122 is a promising lead compound for drug discovery research of GPR88 agonists.
ISSN:0022-2623
1520-4804
DOI:10.1021/acs.jmedchem.2c01983