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

다국어 초록 (Multilingual Abstract)

<P><B>Abstract</B></P> <P>CRA13; a peripheral dual CB<SUB>1</SUB>R/CB<SUB>2</SUB>R agonist with clinically proven analgesic properties, infiltrates into CNS producing adverse effects due to central CB<SUB>1</SUB>R agonism. Such adverse effects might be circumvented by less lipophilic compounds with attenuated CB<SUB>1</SUB>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<SUB>1</SUB>R and CB<SUB>2</SUB>R activity revealed the alcohol metabolite <B>8c</B> as a more potent and more effective CB<SUB>2</SUB>R ligand with attenuated CB<SUB>1</SUB>R affinity relative to CRA13. Also, the alcohol analogue <B>8b</B> and methyl ester <B>12a</B> possessed enhanced CB<SUB>2</SUB>R affinity and reduced CB<SUB>1</SUB>R affinity. The CB<SUB>2</SUB>R binding affinity of alcohol analogue <B>8b</B> was similar to CRA13 while that of methyl ester <B>12a</B> was more potent. <I>In silico</I> study provided insights into the possible molecular interactions that might explain the difference in the elicited biological activity of these compounds.</P> <P><B>Highlights</B></P> <P> <UL> <LI> Design rational based on active metabolite approach. </LI> <LI> Alcoholic, carboxylic metabolites of CRA13 and their analogs were synthesized and evaluated. </LI> <LI> Evaluated compounds were more selective towards CB<SUB>2</SUB>R. </LI> <LI> Compound <B>8c</B> was more potent than CRA13 as CB<SUB>2</SUB>R ligand with attenuated CB<SUB>1</SUB>R affinity. </LI> </UL> </P> <P><B>Graphical abstract</B></P> <P>[DISPLAY OMISSION]</P>