title: Influence of spatial orientation of the C-6-OH group in ring C of morphine derivatives on opioid activity.
abstract: The effect of epimerization on agonist and antagonist activities of morphine and dihydromorphine, and those of their N-allyl, -propyl and -cyclopropylmethyl derivatives, were studied in rat tail flick, hot plate and mice hot plate and in isolated guinea-pig ileum assays, respectively. Using the rat tail flick, hot plate and mice hot plate tests, isomorphine and dihydroisomorphine were observed to produce dose-dependent, naloxone-reversible agonist (antinociceptive) actions, in a similar dose range as their parent molecules (relative potencies: 0.6-1.9). Also, these compounds produced agonist activities in isolated tissue preparations in a naloxone-reversible manner. While the N-substituted derivatives of isomorphine and dihydroisomorphine failed to produce antinociceptive activities in the rat tail flick test, they proved to be strong agonists in the guinea-pig ileum experiments, although the Ke values of naloxone were 5-6 times higher against these compounds than against their N-CH3 counterparts. Both the agonist and antagonist activities of the N-cyclopropylmethyl derivatives were found to be most potent in the guinea-pig ileum. The epimerization of morphine and dihydromorphine and their N-substituted derivatives evoked only slight changes in opioid activities in vitro. In vivo, merely the allyl substitution 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 performed this way evoked, on the one hand, an enhancement of the affinities of compounds to mu-receptors, with simultaneous loss of intrinsic efficacy at these receptors, and, on the other hand, promoted the appearance of an agonist profile on a distinct (kappa) opioid receptor.
authors.affiliation: Department of Pharmacology, Semmelweis University of Medicine, Budapest, Hungary.
authors.forename: T
authors.initials: T
authors.lastname: Friedmann
authors.forename: Z
authors.initials: Z
authors.lastname: Tóth
authors.forename: S
authors.initials: S
authors.lastname: Hosztafi
authors.forename: C S
authors.initials: CS
authors.lastname: Simon
authors.forename: S
authors.initials: S
authors.lastname: Makleit
authors.forename: S
authors.initials: S
authors.lastname: Fürst
mesh_terms: D000698:Analgesia; D000818:Animals; D001667:Binding, Competitive; D004305:Dose-Response Relationship, Drug; D005260:Female; D006168:Guinea Pigs; D007082:Ileum / Q000187:drug effects / Q000378:metabolism; D066298:In Vitro Techniques; D007279:Injections, Subcutaneous; D008297:Male; D051379:Mice; D009020:Morphine / Q000737:chemistry / Q000494:pharmacology; D009022:Morphine Derivatives / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D009130:Muscle, Smooth / Q000187:drug effects / Q000378:metabolism; D009270:Naloxone / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017473:Receptors, Opioid, kappa / Q000187:drug effects* / Q000378:metabolism; D017450:Receptors, Opioid, mu / Q000187:drug effects* / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D009022:Morphine Derivatives; D017473:Receptors, Opioid, kappa; D017450:Receptors, Opioid, mu; D009270:Naloxone; D009020:Morphine