Multiple opioid receptor profile in vitro and activity in vivo of the potent opioid antagonist Win 44,441-3.
Win 44,441-3 is a pure opioid antagonist in rodents in vivo and in isolated tissue preparations in vitro. Win 44,441-3 produced a weak inhibition of electrically-stimulated twitch contractions of the mouse vas deferens (MVD) and guinea-pig ileum (GPI) preparations that was not prevented by naloxone, suggesting that these effects were not mediated through opioid receptors. Similarly, Win 44,441-3 produced a weak, but nonstereoselective antiwrithing effect in the ACh-induced writhing assay. Win 44,441-3 produced a concentration-related antagonism of mu, kappa and delta agonist actions in the MVD and GPI, and was about 10 times more potent than naloxone at each receptor. Also Win 44,441-3 dissociated from mu, kappa and delta receptors more slowly than naloxone. In vivo, Win 44,441-3 produced a dose-related antagonism of morphine and phenazocine-induced antinociception in the tail flick test, and was equipotent with naloxone following s.c. administration. Win 44,441-3 was active orally and demonstrated a significantly longer duration of action than a pharmacologically equivalent oral dose of naloxone vs morphine and phenzaocine in the tail flick test. It can be concluded that Win 44,441-3 is a pure opioid antagonist, 10 times more potent than, with a receptor selectivity profile similar to, that of naloxone in vitro and is of similar potency to, but of longer duration than, naloxone in vivo.
D000818:Animals; D001392:Azocines / Q000494:pharmacology*; D006168:Guinea Pigs; D007082:Ileum / Q000187:drug effects; D008297:Male; D051379:Mice; D009020:Morphine / Q000494:pharmacology; D009119:Muscle Contraction / Q000187:drug effects*; D009270:Naloxone / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000494:pharmacology*; D010620:Phenazocine / Q000494:pharmacology; D011957:Receptors, Opioid / Q000187:drug effects / Q000378:metabolism*; D014649:Vas Deferens / Q000502:physiology
D001392:Azocines; D009292:Narcotic Antagonists; D011957:Receptors, Opioid; D009270:Naloxone; D009020:Morphine; D010620:Phenazocine; C035969:quadazocine