RTI uses cookies to offer you the best experience online. By clicking “accept” on this website, you opt in and you agree to the use of cookies. If you would like to know more about how RTI uses cookies and how to manage them please view our Privacy Policy here. You can “opt out” or change your mind by visiting: http://optout.aboutads.info/. Click “accept” to agree.
Design, synthesis, and structure–activity relationship studies of novel GPR88 agonists (4-substituted-phenyl)acetamides based on the reversed amide scaffold
Rahman, M. T., Guan, D., Hetti Handi, C. L., Decker, A. M., Imler, G. H., Kerr, A., Harris, D. L., & Jin, C. (2023). Design, synthesis, and structure–activity relationship studies of novel GPR88 agonists (4-substituted-phenyl)acetamides based on the reversed amide scaffold. ACS Chemical Neuroscience, 15(1), 169-192. https://doi.org/10.1021/acschemneuro.3c00684
The development of synthetic agonists for the orphan receptor GPR88 has recently attracted significant interest, given the promise of GPR88 as a novel drug target for psychiatric and neurodegenerative disorders. Examination of structure–activity relationships of two known agonist scaffolds 2-PCCA and 2-AMPP, as well as the recently resolved cryo-EM structure of 2-PCCA-bound GPR88, led to the design of a new scaffold based on the “reversed amide” strategy of 2-AMPP. A series of novel (4-substituted-phenyl)acetamides were synthesized and assessed in cAMP accumulation assays as GPR88 agonists, which led to the discovery of several compounds with better or comparable potencies to 2-AMPP. Computational docking studies suggest that these novel GPR88 agonists bind to the same allosteric site of GPR88 that 2-PCCA occupies. Collectively, our findings provide structural insight and SAR requirement at the allosteric site of GPR88 and a new scaffold for further development of GPR88 allosteric agonists.
