Synthesis of oxidative metabolites of CRA13 and their analogs: Identification of CRA13 active metabolites and analogs thereof with selective CB2R affinity

Abstract CRA13; a peripheral dual CB 1 R/CB 2 R agonist with clinically proven analgesic properties, infiltrates into CNS producing adverse effects due to central CB 1 R agonism. Such adverse effects might be circumvented by less lipophilic compounds with attenuated CB 1 R affinity. Metabolism produces less lipophilic metabolites that might be active metabolites. Some CRA13 oxidative metabolites and their analogues were synthesized as less lipophilic CRA13 analogues. Probing their CB 1 R and CB 2 R activity revealed the alcohol metabolite 8c as a more potent and more effective CB 2 R ligand with attenuated CB 1 R affinity relative to CRA13. Also, the alcohol analogue 8b and methyl ester 12a possessed enhanced CB 2 R affinity and reduced CB 1 R affinity. The CB 2 R binding affinity of alcohol analogue 8b was similar to CRA13 while that of methyl ester 12a was more potent. In silico study provided insights into the possible molecular interactions that might explain the difference in the elicited biological activity of these compounds.