The pharmacological significance of the spatial orientation of C-6-OH group in ring C of morphine

Abstract The effect of epimerization on agonist and antagonist activities of morphine and dihydromorphine, and those of their N-allyl, -propyl, -and cyclopropylmethyl, (CPM) derivatives were studied in rat tail flick (RTF), and in isolated guinea pig ileum (GPI) assays, resp. Isomorphine and dihydroisomorphine were observed to produce dose dependent agonist (antinociceptive) actions, in RTF, in a similar dose range, than their parent molecules (relative potencies: 0.6–1.9). Also, these compounds produced agonist activities in GPI in a naloxone reversible manner. While the N-substituted derivatives of isomorphine and dihydroisomorphine failed to produced antinociceptive activities in RTF, they proved to be strong agonists in GPI, although the Ke values of naloxone was 5–6 times higher against these compunds, than against their N-CH 3 counterparts. While the epimerization of morphine and dihydromorphine and their N-substituted derivatives evoked only slight changes in opioid activities in vitro, substantial changes in opioid profile were observed when N-methyl was replaced by allyl-,propyl or CPM. Changes performed this way one hand, evoked an enhancement of the affinities of compounds to mu receptors, with simultaneous loss of intrinsic efficacy at these receptors, on the other hand, they promote the appearence of agonist profile on a distinct (kappa) opioid receptor.