RECEPTOR-BINDING, ANTAGONIST, AND WITHDRAWAL PRECIPITATING PROPERTIES OF OPIATE ANTAGONISTS
RECEPTOR-BINDING, ANTAGONIST, AND WITHDRAWAL PRECIPITATING PROPERTIES OF OPIATE ANTAGONISTS
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DOI：
10.1016/0024-3205(83)90325-9
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发表时间：
1983-01-01
期刊：
影响因子：
6.1
通讯作者：
WOODS, JH
中科院分区：
文献类型：
--
作者：
VALENTINO, RJ;KATZ, JL;WOODS, JH
研究了一些阿片拮抗剂和其中一些药物的右旋异构体对急性阿片对从阿片类药物未使用过的豚鼠分离的回肠的作用的拮抗作用、对从吗啡依赖的豚鼠分离的回肠的戒断收缩的沉淀作用、对吗啡依赖的恒河猴[Macaca mulatta]的戒断的沉淀作用以及对3 H-埃托啡与大鼠脑膜结合的立体特异性置换作用。除d-纳洛酮外，所有化合物均取代3 H-埃托啡。除d-纳洛酮、纳洛啡和季纳洛啡外，所有拮抗剂均引起吗啡依赖豚鼠离体回肠收缩。化合物置换3 H-埃托啡结合的IC 50 [中位抑制浓度]值与其回肠拮抗作用的Ke [拮抗剂效力]值（r = 0.95）和其在该制剂中引起收缩的EC 50 [中位有效浓度]值（r = 0.92）均具有良好的相关性。一般来说，沉淀一半最大挛缩所需的拮抗剂浓度是拮抗剂的Ke值的30倍。大多数阿片受体拮抗剂也沉淀戒断时，给药吗啡依赖的恒河猴和他们的体内效力与他们在回肠（与Ke：r = 0.95;与EC 50：r = 0.99），并在取代3 H-埃托啡（r = 0.95）在体外效力良好相关。纳洛酮的季铵衍生物仅在体外是有效的阿片拮抗剂，并且在吗啡依赖的恒河猴中对催促戒断无效。显然，3 H-埃托啡标记的受体位点与参与急性阿片作用拮抗和戒断沉淀的受体位点相同。
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 [Macaca mulatta] 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. The IC50 [median inhibitory concentration] values of the compounds for displacing 3H-etorphine binding were well correlated with both their Ke [antagonist potency] values for antagonism in the ileum (r = 0.95) and with their EC50 [median effective concentration] 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 EC50: r = 0.99) and in displacing 3H-etorphine (r = 0.95). The quaternary derivative of naltrexone was an effective opiate antagonist only in vitro and was ineffective in precipitating withdrawal in morphine-dependent rhesus monkeys. Evidently, the receptor sites labeled by 3H-etorphine are the same as those involved in antagonism of acute opiate actions and in precipitation of withdrawal.