RTI International, 3040 Cornwallis Road, Research Triangle Park, NC, USA.
RTI International, 3040 Cornwallis Road, Research Triangle Park, NC, USA.
Life Sci. 2014 Feb 27;97(1):55-63. doi: 10.1016/j.lfs.2013.09.011. Epub 2013 Sep 23.
Originally synthesized for research purposes, indole- and pyrrole-derived synthetic cannabinoids are the most common psychoactive compounds contained in abused products marketed as "spice" or "herbal incense." While CB1 and CB2 receptor affinities are available for most of these research chemicals, in vivo pharmacological data are sparse. In mice, cannabinoids produce a characteristic profile of dose-dependent effects: antinociception, hypothermia, catalepsy and suppression of locomotion. In combination with receptor binding data, this tetrad battery has been useful in evaluation of the relationship between the structural features of synthetic cannabinoids and their in vivo cannabimimetic activity. Here, published tetrad studies are reviewed and additional in vivo data on synthetic cannabinoids are presented. Overall, the best predictor of likely cannabimimetic effects in the tetrad tests was good CB1 receptor affinity. Further, retention of good CB1 affinity and in vivo activity was observed across a wide array of structural manipulations of substituents of the prototypic aminoalkylindole molecule WIN55,212-2, including substitution of an alkyl for the morpholino group, replacement of an indole core with a pyrrole or phenylpyrrole, substitution of a phenylacetyl or tetramethylcyclopropyl group for JWH-018's naphthoyl, and halogenation of the naphthoyl group. This flexibility of cannabinoid ligand-receptor interactions has been a particular challenge for forensic scientists who have struggled to identify and regulate each new compound as it has appeared on the drug market. One of the most pressing future research needs is determination of the extent to which the pharmacology of these synthetic cannabinoids may differ from those of classical cannabinoids.
最初为研究目的而合成的吲哚和吡咯衍生的合成大麻素是在作为“香料”或“草药熏香”销售的滥用产品中最常见的具有致幻作用的化合物。虽然大多数这些研究用化学物质都具有 CB1 和 CB2 受体亲和力，但体内药理学数据却很少。在小鼠中，大麻素会产生特征性的剂量依赖性作用谱：镇痛、体温过低、僵直和运动抑制。结合受体结合数据，这种四联体电池在评估合成大麻素的结构特征与其体内大麻样活性之间的关系方面非常有用。在这里，综述了已发表的四联体研究，并提供了关于合成大麻素的额外体内数据。总体而言，良好的 CB1 受体亲和力是预测四联体测试中可能出现的大麻样作用的最佳指标。此外，在对原型氨基烷基吲哚分子 WIN55,212-2 的取代基进行广泛的结构修饰时，观察到良好的 CB1 亲和力和体内活性的保留，包括用吗啉基取代烷基、用吡咯或苯基吡咯取代吲哚核、用苯乙酰基或四甲基环丙基取代 JWH-018 的萘甲酰基，以及萘甲酰基的卤化。这种大麻素配体-受体相互作用的灵活性一直是法医科学家面临的一个特别挑战，他们一直在努力识别和监管每种新化合物，因为它们出现在毒品市场上。未来最紧迫的研究需求之一是确定这些合成大麻素的药理学在多大程度上可能与经典大麻素不同。
