Improvement of the Metabolic Stability of GPR88 Agonist RTI-13951-33: Design, Synthesis, and Biological Evaluation - Université de Picardie Jules Verne Accéder directement au contenu
Article Dans Une Revue Journal of Medicinal Chemistry Année : 2023

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

Résumé

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.

Domaines

Toxicologie
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Dates et versions

hal-03980716 , version 1 (09-02-2023)

Identifiants

Citer

Md Toufiqur Rahman, Ann Decker, Sami Ben Hamida, David Perrey, Hetti Handi Chaminda Lakmal, et al.. Improvement of the Metabolic Stability of GPR88 Agonist RTI-13951-33: Design, Synthesis, and Biological Evaluation. Journal of Medicinal Chemistry, 2023, ⟨10.1021/acs.jmedchem.2c01983⟩. ⟨hal-03980716⟩
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