Cannabinoid pharmacological properties common to other centrally acting drugs
Cannabinoid pharmacological properties common to other centrally acting drugs
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DOI：
10.1016/s0014-2999(03)01856-9
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发表时间：
2003-06-27
影响因子：
5
通讯作者：
Martin, BR
中科院分区：
文献类型：
--
作者：
Wiley, JL;Martin, BR
大麻素在小鼠体内产生特征性作用，包括抑制自发活动、抗伤害感受、体温过低和僵住症。测量这四个属性，通常被称为四分体测试，在建立大麻素CB 1受体的大麻素的结构-活性关系中发挥了关键作用。本研究的目的是确定作用于非大麻素CB 1受体的药物是否产生类似的药理学特征。在注射Delta（9）-四氢大麻酚和从其他药物类别中选择的药物后，在该范例中测试小鼠。δ（9）-四氢大麻酚剂量依赖性地产生了所有四种效应，大麻素CB 1受体拮抗剂N-（哌啶-1-基）-5-（4-氯苯基）-1-（2，4-二氯苯基）-4-甲基-1H-吡唑-3-甲酰胺盐酸盐（SR 141716 A）可逆转该效应。安非他明、东莨菪碱、吗啡、地昔帕明、匹莫齐特、戊巴比妥、乙醇和地西泮在至少一项试验中没有完全活性。抗精神病药物在四分体试验中表现出与大麻素最大的相似性，尽管也有明显的差异。氯氮平、氟哌啶醇、硫利达嗪和氯丙嗪（但不是匹莫齐特）在所有四项试验中均具有完全活性;然而，与Delta（9）-四氢大麻酚不同，SR 141716 A未阻断其作用。此外，尽管抗精神病药物产生了近100%的僵住症，但由δ（9）-四氢大麻酚产生的最大僵住症为60%。抗精神病药物在小鼠中产生这些作用的机制尚不确定，但它不同于介导大麻素作用的大麻素CB 1受体激活。虽然之前的研究结果表明，四分体测试是检查大麻素CB 1受体激动剂结构-活性关系的有用工具，但目前的结果表明，在寻找新型大麻素受体时必须谨慎使用它们。(C)2003 Elsevier Science B.V保留所有权利。
Cannabinoids produce a characteristic profile of in vivo effects in mice, including suppression of spontaneous activity, antinociception, hypothermia, and catalepsy. Measurement of these four properties, commonly referred to as the tetrad test, has played a key role in establishing the structure-activity relationship of cannabinoids acting at cannabinoid CB1 receptors. The purpose of this study was to determine whether drugs acting at noncannabinoid CB1 receptors produced a similar pharmacological profile. Mice were tested in this paradigm after being injected with Delta(9)-tetrahydrocannabinol and selected drugs from other drug classes. Delta(9)-Tetrahydrocannabinol dose-dependently produced all four effects with reversal by the cannabinoid CB1 receptor antagonist N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide hydrochloride (SR 141716A). Amphetamine, scopolamine, morphine, desipramine, pimozide, pentobarbital, ethanol, and diazepam were not fully active in at least one of the tests. Antipsychotics showed the greatest similarity to those of cannabinoids in the tetrad tests, although there were also distinct differences. Clozapine, haloperidol, thioridazine, and chlorpromazine (but not pimozide) were fully active in all four tests; however, unlike with Delta(9)-tetrahydrocannabinol, their effects were not blocked by SR 141716A. Further, whereas antipsychotics produced nearly 100% catalepsy, maximal catalepsy produced by Delta(9)-tetrahydrocannabinol was 60%. The mechanism through which antipsychotics produce these effects in mice is uncertain, but it differs from cannabinoid CB1 receptor activation that mediates the effects of cannabinoids. While results of previous research suggest that the tetrad tests are a useful tool in examination of structure-activity relationships of cannabinoid CB1 receptor agonists, the present results suggest that they must be used cautiously in the search for novel cannabinoid receptors. (C) 2003 Elsevier Science B.V All rights reserved.