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.