Design, Synthesis, and Structure-Activity Relationship Studies of (4-Alkoxyphenyl)glycinamides and Bioisosteric 1,3,4-Oxadiazoles as GPR88 Agonists.
|Title||Design, Synthesis, and Structure-Activity Relationship Studies of (4-Alkoxyphenyl)glycinamides and Bioisosteric 1,3,4-Oxadiazoles as GPR88 Agonists.|
|Publication Type||Journal Article|
|Year of Publication||2020|
|Authors||Rahman MToufiqur, Decker AM, Langston TL, Mathews KM, Laudermilk L, Maitra R, Ma W, Darcq E, Kieffer BL, Jin C|
|Journal||J Med Chem|
|Date Published||2020 12 10|
|Keywords||Animals, Drug Design, Glycine, Male, Mice, Knockout, Molecular Structure, Oxadiazoles, Rats, Long-Evans, Receptors, G-Protein-Coupled, Solubility, Structure-Activity Relationship|
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.
|Alternate Journal||J Med Chem|
|PubMed Central ID||PMC7737621|
|Grant List||R01 AA022235 / AA / NIAAA NIH HHS / United States |
R01 AA026820 / AA / NIAAA NIH HHS / United States
R21 MH103708 / MH / NIMH NIH HHS / United States