THE PHARMACOLOGICAL SIGNIFICANCE OF THE SPATIAL ORIENTATION OF C-6-OHGROUP IN RING-C OF MORPHINE

The effect of epimerization on agonist and antagonist activities of mo rphine and dihydromorphine, and those of their N-allyl, -propyl, -and cyclopropylmethyl, (CPM) derivatives were studied in rat tail flick (R TF), 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 thei r parent molecules (relative potencies: 0.6-1.9). Also, these compound s produced agonist activities in GPI in a naloxone reversible manner. While the N-substituted derivatives of isomorphine and dihydroisomorph ine failed to produce antinociceptive activities in RTF, they proved t o be strong agonists in GPI, although the Ke values of naloxone was 5- 6 times higher against these compounds, than against their N-CH3 count erparts. While the epimerization of morphine and dihydromorphine acid their N-substituted derivatives evoked only slight changes in opioid a ctivities in vitro, substantial changes in opioid profile were observe d when N-methyl was replaced by allyl-,propyl or CPM. Changes performe d this way one hand, evoked an enhancement of the affinities of compou nds to mu receptors, with simultaneous loss of intrinsic efficacy at t hese receptors, on the other hand, they promote the appearence of agon ist profile on a distinct (kappa) opioid receptor.