Design, synthesis, and structure-activity relationship studies of (4-alkoxyphenyl)glycinamides and bioisosteric 1,3,4-oxadiazoles as GPR88 agonists
Rahman, M. T., Decker, A. M., Langston, T. L., Mathews, K. M., Laudermilk, L., Maitra, R., Ma, W., Darcq, E., Kieffer, B. L., & Jin, C. (2020). Design, synthesis, and structure-activity relationship studies of (4-alkoxyphenyl)glycinamides and bioisosteric 1,3,4-oxadiazoles as GPR88 agonists. Journal of Medicinal Chemistry, 63(23), 14989-15012. Advance online publication. https://doi.org/10.1021/acs.jmedchem.0c01581
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 a concentration of 100 μM. In vivo pharmacokinetic testing of 90 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.