Open AccessDesign, Synthesis, and Structure–Activity Relationship Studies of (4-Alkoxyphenyl)glycinamides and Bioisosteric 1,3,4-Oxadiazoles as GPR88 Agonists
Author(s) -
Toufiqur Rahman,
Ann M. Decker,
Tiffany L. Langston,
Kelly M. Mathews,
Lucas Laudermilk,
Rangan Maitra,
Weiya Ma,
Emmanuel Darcq,
Brigitte L. Kieffer,
Chunyang Jin
Publication year - 2020
Publication title -
journal of medicinal chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.01
H-Index - 261
eISSN - 1520-4804
pISSN - 0022-2623
DOI - 10.1021/acs.jmedchem.0c01581
Subject(s) - chemistry , lipophilicity , in vivo , pharmacology , oxadiazole , agonist , pharmacokinetics , partial agonist , potency , stereochemistry , in vitro , receptor , biochemistry , organic chemistry , medicine , microbiology and biotechnology , biology
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 EC 50 of 59 nM in the GPR88 overexpressing cell-based cAMP assay. In addition, 84 had an EC 50 of 942 nM in the [ 35 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 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.