Design, Synthesis, and Structure-Activity Relationship Studies of (4-Alkoxyphenyl)glycinamides and Bioisosteric 1,3,4-Oxadiazoles as GPR88 Agonists.

ABSTRACT: 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., 31) and the corresponding 1,3,4-oxadiazole bioisosteres derived from the 2-AMPP scaffold (1) as GPR88 agonists. The 5-amino-1,3,4-oxadiazole derivatives (84, 88-90) had significantly improved potency and lower lipophilicity compared to 2-AMPP. Compound 84 had an EC₅₀ of 59 nM in the GPR88 overexpressing cell-based cAMP assay. In addition, 84 had an EC₅₀ of 942 nM in the [³⁵S]GTPγS binding assay using mouse striatal membranes but was inactive in membranes from GPR88 knockout mice, even at

SUBMITTER: Rahman MT 

PROVIDER: S-EPMC7737621 | biostudies-literature | 2020 Dec

REPOSITORIES: biostudies-literature