Design, Synthesis, and Structure-Activity Relationship Studies of (4-Alkoxyphenyl)glycinamides and Bioisosteric 1,3,4-Oxadiazoles as GPR88 Agonists.
Fiche publication
Date publication
décembre 2020
Journal
Journal of medicinal chemistry
Auteurs
Membres identifiés du Cancéropôle Est :
Dr DARCQ Emmanuel
Tous les auteurs :
Rahman MT, Decker AM, Langston TL, Mathews KM, Laudermilk L, Maitra R, Ma W, Darcq E, Kieffer BL, Jin C
Lien Pubmed
Résumé
Increasing evidence implicates the orphan G protein-coupled receptor 88 (GPR88) in a number of striatal-associated disorders. In this study, we report the design and synthesis of a series of novel (4-alkoxyphenyl)glycinamides (e.g., ) and the corresponding 1,3,4-oxadiazole bioisosteres derived from the 2-AMPP scaffold () as GPR88 agonists. The 5-amino-1,3,4-oxadiazole derivatives (, ) had significantly improved potency and lower lipophilicity compared to 2-AMPP. Compound had an EC of 59 nM in the GPR88 overexpressing cell-based cAMP assay. In addition, had an EC of 942 nM in the [S]GTPγS binding assay using mouse striatal membranes but was inactive in membranes from GPR88 knockout mice, even at a concentration of 100 μM. In vivo pharmacokinetic testing of in rats revealed that the 5-amino-1,3,4-oxadiazole analogues may have limited brain permeability. Taken together, these results provide the basis for further optimization to develop a suitable agonist to probe GPR88 functions in the brain.
Mots clés
Animals, Drug Design, Glycine, analogs & derivatives, Male, Mice, Knockout, Molecular Structure, Oxadiazoles, chemical synthesis, Rats, Long-Evans, Receptors, G-Protein-Coupled, agonists, Solubility, Structure-Activity Relationship
Référence
J Med Chem. 2020 12 10;63(23):14989-15012