SYNTHESIS AND BIOLOGICAL EVALUATION OF 14-ALKOXYMORPHINANS .11. 3-HYDROXYCYPRODIME AND ANALOGS - OPIOID ANTAGONIST PROFILE IN COMPARISON TOCYPRODIME

A series of 3-hydroxy-substituted analogues (3-7) of the mu selective opioid antagonist cyprodime has been synthesized in order to evaluate the role of a hydroxy group at C-3 concerning mu opioid antagonist sel ectivity. Compounds 3-7 were tested in bioassays (electrical stimulate d mouse vas deferens preparation and myenteric-plexus longitudinal mus cle preparation of the guinea pig ileum) and opioid receptor binding a ssays. Antagonism of mu receptor-mediated responses induced by the mu selective agonist DAMGO afforded equilibrium dissociation constants in the mouse vas deferens preparation (K-e values) for compounds 3-7 whi ch agreed closely with their affinities as determined by opioid recept or binding assays (K-i values). At kappa and delta receptors differenc es were apparent. Although the compounds had high affinity for both ka ppa and delta receptors in opioid receptor binding, they were very poo r at antagonizing agonist responses mediated by kappa and particularly delta agonists in the mouse vas deferens preparation. None of the com pounds tested showed agonist potency in the mouse vas deferens prepara tion or the myenteric-plexus longitudinal muscle preparation of the gu inea pig ileum.