Multiple opioid receptor profile in vitro and activity in vivo of the potent opioid antagonist win 44,441-3

Abstract

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 non- stereoselective antiwrithing effect in the ACh-induced writhing assay. Win 44,441-3 produced a concentration-related antagonism of μ, κ and δ 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 μ, κ and δ 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 phenazocine 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 . Win 44,441-3 (2α,6α,11S ∗)-(-)-1-cyclopentyl-5-(1,2,3,4,5,6-hexahydro-8-hydroxy-3,6,11- trimethyl-2,6-methano-3-benzazocin-11-yl)-3-pentanone methane sulfonate (salt) is a potent opioid antagonist which, during recent years, has been described by investigators in the area of multiple opioid receptors as a selective κ antagonist. However, although it has been reported (1) that Win 44,441-3 is more potent than naloxone at κ receptors, it has not been demonstrated that this compound interacts selectively with κ receptors. Since the degree of selectivity inherent in a given compound is crucial to the conclusions that may be drawn from studies that use selective antagonists as pharmacological tools, the present report determines to clarify the opioid receptor profile of Win 44,441-3 and demonstrate that whilst Win 44,441-3 is indeed more potent than naloxone at κ receptors, its receptor selectivity is similar to that of naloxone. Win 44,441-3 was studied in vitro using the guinea-pig ileum (GPI) and mouse vas deferens (MVD) preparations, and in vivo using the mouse acethylcholine-(ACh) induced writhing and rat intracarotid bradykinin (BRDK) and tail flick assays.