| Abstract
| - Novel 14-alkoxy-substituted (e.g. allyloxy, benzyloxy, naphthylmethoxy) morphinan-6-onederivatives were synthesized and biologically evaluated. Compounds 6−9 and 11 displayedaffinities in the subnanomolar range to μ opioid receptors which were comparable to 14-O-methyloxymorphone (1) and 14-methoxymetopon (3), and higher than oxymorphone (2). Opioidbinding affinity was sensitive to the character and length of the substituent in position 14. Insmooth muscle preparations they behaved as potent agonists. Antinociceptive potencies ofcompounds 6−11 in the hot-plate test after sc administration in mice were considerably greaterthan the potency of morphine. In the colonic propulsion test, the most potent analgesic compound7 showed negligible constipating activity at the analgesic dose. These findings provide furtherevidence that the nature of the substituent at position 14 has a major impact on the abilitiesof morphinans to interact with opioid receptors. Introduction of a 5-methyl group has nosignificant effect on in vitro biological activities, but resulted in decreased antinociceptivepotency.
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