title: Receptor binding, antagonist, and withdrawal precipitating properties of opiate antagonists.
abstract: A number of opiate antagonists and the dextro isomers of some of these drugs were studied for antagonism of acute opiate effects on ilea isolated from opiate-naive guinea pigs, precipitation of a withdrawal contraction of ilea isolated from morphine-dependent guinea pigs, precipitation of withdrawal in morphine-dependent rhesus monkeys and stereospecific displacement of 3H-etorphine binding to rat-brain membranes. With the exception of d-naloxone, all of the compounds displaced 3H-etorphine. With the exception of d-naloxone, nalorphine, and quaternary nalorphine, all of the antagonists caused a contraction of ilea isolated from morphine-dependent guinea pigs. Moreover, the IC 50 values of the compounds for displacing 3H-etorphine binding were well correlated with both their Ke values for antagonism in the ileum (r = 0.95) and with their EC 50 values for precipitating a contraction in this preparation (r = 0.92). Generally, the concentration of antagonist necessary to precipitate half maximal contracture was 30-fold greater than the Ke value of the antagonist. Most of the opiate antagonists also precipitated withdrawal when administered to morphine-dependent rhesus monkeys and their in vivo potencies were well correlated with their in vitro potencies in ileum (with Ke: r = 0.95; with EC 50: r = 0.99) and in displacing 3H-etorphine (r = 0.95). The quaternary derivative of naltrexone, however, was an effective opiate antagonist only in vitro, and was ineffective in precipitating withdrawal in morphine-dependent rhesus monkeys. These results suggest that the receptor sites labeled by 3H-etorphine are the same as those involved in antagonism of acute opiate actions and in precipitation of withdrawal.
mesh_terms: D000818:Animals; D001667:Binding, Competitive; D001921:Brain / Q000378:metabolism*; D002462:Cell Membrane / Q000378:metabolism; D005048:Etorphine / Q000378:metabolism; D006801:Humans; D007082:Ileum / Q000187:drug effects; D007700:Kinetics; D008253:Macaca mulatta; D008297:Male; D009021:Morphine Dependence / Q000503:physiopathology; D009119:Muscle Contraction / Q000187:drug effects; D009270:Naloxone / Q000378:metabolism; D009292:Narcotic Antagonists / Q000378:metabolism / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains; D011957:Receptors, Opioid / Q000187:drug effects / Q000378:metabolism*; D013329:Structure-Activity Relationship; D013375:Substance Withdrawal Syndrome
chemical_list: D009292:Narcotic Antagonists; D011957:Receptors, Opioid; D009270:Naloxone; D005048:Etorphine