Synthesis and structure-opioid activity relationships of trans-(+/-)-3,4-dichloro-N-methyl-N-[4- or 5-hydroxy-2-(1-pyrrolidiny)cyclohexyl]benzeneacetamides.

To explore the effects of attaching a hydroxy function to the cyclohexane ring of kappa-selective opioid N-[2-(1-pyrrolidinyl)cyclohexyl]benzeneacetamides, trans-(+/-)-3,4-dichloro-N-methyl-N-[4- or 5-hydroxy-2-(1-pyrrolidiny)cyclohexyl]benzeneacetamides (1-4) and their benzoates (5-8) have been synthesized in a divergent and stereoselective manner. When compared with the parent compound U-50488, hydroxy derivatives 1-4 maintained high selectivity towards the kappa-opioid receptor (mu/kappa ratio = 24 to > 91); while displaying significant reduction in binding affinity (Ki,kappa = 75-218 nM). The lowest kappa-affinity was observed with compound 4, where the hydroxy group is attached at the 5-axial or 5-beta position. Further reduction in kappa-affinity was observed when the hydroxy function was benzoylated. However, the 4 beta, 5 alpha, and 5 beta isomers (6-8) maintained varying degrees of kappa-selectivity; the 4 alpha-isomer compound 5, with its benzoate moiety situated at the 4-axial position is now a moderately potent mu-selective opioid (Ki,mu = 168 nM, mu/kappa = 0.076). The result suggest the importance of lipophilicity in binding to opioid receptors and the presence of a specific lipophilic binding site on the mu-opioid receptor.