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

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.