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

CRA13; a peripheral dual CBR/CBR agonist with clinically proven analgesic properties, infiltrates into CNS producing adverse effects due to central CBR agonism. Such adverse effects might be circumvented by less lipophilic compounds with attenuated CBR 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 CBR and CBR activity revealed the alcohol metabolite 8c as a more potent and more effective CBR ligand with attenuated CBR affinity relative to CRA13. Also, the alcohol analogue 8b and methyl ester 12a possessed enhanced CBR affinity and reduced CBR affinity. The CBR 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.