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首页> 外文期刊>Life sciences >New morphinan derivatives with negligible psychotropic effects attenuate convulsions induced by maximal electroshock in mice.
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New morphinan derivatives with negligible psychotropic effects attenuate convulsions induced by maximal electroshock in mice.

机译：新的吗啡衍生物具有可忽略的精神作用，可减轻小鼠最大电击诱发的惊厥。

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Interest in dextromethorphan (DM) has been renewed because of its anticonvulsant and neuroprotective properties. However, DM at supra-antitussive doses can produce psychotomimetic effects in humans. Recently, we demonstrated that DM exerts psychotropic effects in mice [Neurosci. Lett. 288 (2000) 76, Life Sci. 69 (2001) 615]. We synthesized a series of compounds with a modified morphinan ring system, with the intention of developing compounds that retain the anticonvulsant activity with weak psychotropic effects [Bioorg. Med. Chem. Lett. 11 (2001) 1651]. In order to extend our understanding of the pharmacological intervention of these morphinans, we assessed their behavioral effects, and then examined whether they exert protective effects on maximal electroshock convulsions (MES) in mice. Repeated treatment (20 or 40 mg/kg, i.p./day x 7) with DM or dextrorphan (a major metabolite of DM; DX) significantly enhanced locomotor activity in a dose-related manner. This locomotor stimulation was accentuated more in the animals treated with DX, and might be comparable to that of phencyclidine (PCP). By contrast, treatment with a metabolite of DM [3-methoxymorphinan (3MM) or 3-hydroxymorphinan (3HM)], 3-allyloxy-17-methylmorphinan (CPK-5), or 3-cyclopropylmethoxy-17-methylmorphinan (CPK-6) did not significantly alter locomotor activity or patterns. The behavioral effects mediated by these morphinans and PCP paralleled the effects of conditioned place preference. DM, DX, CPK-5, and CPK-6 had anticonvulsant effects against MES, while 3MM and 3HM did not show any anticonvulsant effects. We found that DM, DX, CPK-5 and CPK-6 were high-affinity ligands at sigma(1) receptors, while they all had low affinity at sigma(2) receptors. DX had relatively higher affinity for the PCP sites than DM. By contrast, CPK-5 and CPK-6 had very low affinities for PCP sites, suggesting that PCP sites are not requisites for their anticonvulsant actions. Our results suggest that the new morphinan analogs are promising anticonvulsants that are devoid of PCP-like behavioral side effects, and their anticonvulsant actions may be, in part, mediated via sigma(1) receptors.
机译：由于右美沙芬（DM）具有抗惊厥和神经保护特性，引起了人们的兴趣。但是，超镇定剂量的DM可以在人体中产生拟精神病药物的作用。近来，我们证明了DM在小鼠中发挥精神作用[Neurosci。来吧288（2000）76，生命科学。 69（2001）615]。我们合成了一系列具有修饰的吗啡喃环系统的化合物，以期开发出保留抗惊厥活性，弱精神作用的化合物[Bioorg。中化学来吧11（2001）1651]。为了扩展我们对这些吗啡类药物的药理干预的了解，我们评估了它们的行为作用，然后研究了它们是否对小鼠最大的电击惊厥（MES）发挥保护作用。用DM或右美沙芬（DM的主要代谢产物; DX）重复治疗（20或40 mg / kg，腹膜内/天x 7），以剂量相关的方式显着增强运动能力。在用DX处理的动物中，这种运动刺激更加明显，可能与苯环利定（PCP）相当。相比之下，用DM [3-甲氧基吗啡喃（3MM）或3-羟基吗啡喃（3HM），3-烯丙氧基-17-甲基吗啡喃（CPK-5）或3-环丙基甲氧基-17-甲基吗啡喃（CPK-6）的代谢物处理）没有显着改变运动活动或模式。这些吗啡喃和五氯苯酚介导的行为影响与条件性位置偏爱的影响平行。 DM，DX，CPK-5和CPK-6对MES具有抗惊厥作用，而3MM和3HM没有显示任何抗惊厥作用。我们发现DM，DX，CPK-5和CPK-6是sigma（1）受体的高亲和力配体，而它们对sigma（2）受体的亲和力均很低。 DX对PCP站点的亲和力比DM高。相比之下，CPK-5和CPK-6对PCP部位的亲和力很低，这表明PCP部位不是其抗惊厥作用的必要条件。我们的结果表明，新的吗啡喃类似物是有前途的抗惊厥药，没有PCP样的行为副作用，并且它们的抗惊厥作用可能部分是通过sigma（1）受体介导的。

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