INFLUENCE OF SPATIAL ORIENTATION OF THE C-6-OH GROUP IN RING-C OF MORPHINE DERIVATIVES ON OPIOID ACTIVITY

The effect of epimerization on agonist and antagonist activities of mo rphine and dihydromorphine, and those of their N-allyl, -propyl and -c yclopropylmethyl derivatives, were studied in rat tail flick, hot plat e and mice hot plate and in isolated guineapig ileum assays, respectiv ely. Using the rat tail flick, hot plate and mice hot plate tests, iso morphine and dihydroisomorphine were observed to produce dose-dependen t, naloxone-reversible agonist (antinociceptive) actions, in a similar dose range as their parent molecules (relative potencies: 0.6-1.9). A lso, these compounds produced agonist activities in isolated tissue pr eparations in a naloxone-reversible manner. While the N-substituted de rivatives of isomorphine and dihydroisomorphine failed to produce anti nociceptive activities in the rat tail flick test, they proved to be s trong agonists in the guinea-pig ileum experiments, although the K-c v alues of naloxone were 5-6 times higher against these compounds than a gainst their N-CH3 counterparts. Both the agonist and antagonist activ ities of the N-cyclopropylmethyl derivatives were found to be most pot ent in the guinea-pig ileum. The epimerization of morphine and dihydro morphine and their N-substituted derivatives evoked only slight change s in opioid activities in vitro. In vivo, merely the allyl substitutio n on nitrogen influenced the antagonist activities of epimer pairs. In contrast, substantial changes in opioid profile were observed when N- methyl was replaced by allyl-, propyl- or cyclopropylmethyl. Changes p erformed this way evoked, on the one hand, an enhancement of the affin ities of compounds to mu-receptors, with simultaneous loss of intrinsi c efficacy at these receptors, and, on the other hand, promoted the ap pearance of an agonist profile on a distinct (kappa) opioid receptor.