Synthesis and biological evaluation of 14-alkoxymorphinans. 22.(1) Influence of the 14-alkoxy group and the substitution in position 5 in 14-alkoxymorphinan-6-ones on in vitro and in vivo activities.
Novel 14-alkoxy-substituted (e.g. allyloxy, benzyloxy, naphthylmethoxy) morphinan-6-one derivatives were synthesized and biologically evaluated. Compounds 6-9 and 11 displayed affinities in the subnanomolar range to mu opioid receptors which were comparable to 14-O-methyloxymorphone (1) and 14-methoxymetopon (3), and higher than oxymorphone (2). Opioid binding affinity was sensitive to the character and length of the substituent in position 14. In smooth muscle preparations they behaved as potent agonists. Antinociceptive potencies of compounds 6-11 in the hot-plate test after sc administration in mice were considerably greater than the potency of morphine. In the colonic propulsion test, the most potent analgesic compound 7 showed negligible constipating activity at the analgesic dose. These findings provide further evidence that the nature of the substituent at position 14 has a major impact on the abilities of morphinans to interact with opioid receptors. Introduction of a 5-methyl group has no significant effect on in vitro biological activities, but resulted in decreased antinociceptive potency.
Lattanzi
Roberta
R
Department of Human Physiology and Pharmacology, University 'La Sapienza', P.le Aldo Moro 5, I-00185 Rome, Italy.
Spetea
Mariana
M
Schüllner
Falko
F
Rief
Silvia B
SB
Krassnig
Roland
R
Negri
Lucia
L
Schmidhammer
Helmut
H
D000701:Analgesics, Opioid / Q000009:adverse effects / Q000138:chemical synthesis* / Q000494:pharmacology; D000818:Animals; D001921:Brain / Q000378:metabolism; D005769:Gastrointestinal Motility / Q000187:drug effects; D006168:Guinea Pigs; D066298:In Vitro Techniques; D007421:Intestine, Small / Q000187:drug effects / Q000502:physiology; D008297:Male; D051379:Mice; D009019:Morphinans / Q000009:adverse effects / Q000138:chemical synthesis* / Q000494:pharmacology; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects / Q000502:physiology; D010111:Oxymorphone / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017465:Receptors, Opioid, delta / Q000819:agonists; D017473:Receptors, Opioid, kappa / Q000819:agonists; D017450:Receptors, Opioid, mu / Q000819:agonists*; D013329:Structure-Activity Relationship; D014649:Vas Deferens / Q000187:drug effects / Q000502:physiology
C500851:14-benzyloxy-4,5-epoxy-3-hydroxy-17-methylmorphinan-6-one; D000701:Analgesics, Opioid; D009019:Morphinans; D017465:Receptors, Opioid, delta; D017473:Receptors, Opioid, kappa; D017450:Receptors, Opioid, mu; D010111:Oxymorphone