Moving around the molecule: relationship between chemical structure and in vivo activity of synthetic cannabinoids.
Moving around the molecule: relationship between chemical structure and in vivo activity of synthetic cannabinoids.
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DOI：
10.1016/j.lfs.2013.09.011
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发表时间：
2014-02-27
期刊：
影响因子：
6.1
通讯作者：
Huffman, John W.
中科院分区：
文献类型：
--
作者：
Wiley, Jenny L.;Marusich, Julie A.;Huffman, John W.
关键词：
吲哚和吡咯衍生的合成大麻素最初是为了研究目的而合成的，是作为“香料”或“草药香”销售的滥用产品中最常见的精神活性化合物。虽然大多数研究化学品都具有 CB1 和 CB2 受体亲和力，但体内药理学数据却很少。在小鼠中，大麻素产生剂量依赖性效应的特征：镇痛、体温过低、僵直和运动抑制。结合受体结合数据，这种四联体电池可用于评估合成大麻素的结构特征与其体内大麻模拟活性之间的关系。在此，回顾了已发表的四分体研究，并提供了有关合成大麻素的其他体内数据。总体而言，四分体测试中可能的大麻模拟效应的最佳预测因素是良好的 CB1 受体亲和力。此外，在原型氨基烷基吲哚分子WIN55,212-2的取代基的多种结构操作中观察到良好的CB1亲和力和体内活性的保留，包括用烷基取代吗啉代基团、用吡咯或苯基吡咯取代吲哚核心、取代苯乙酰基或四甲基环丙基 JWH-018的萘甲酰基，以及萘甲酰基的卤化。大麻素配体-受体相互作用的这种灵活性对于法医科学家来说是一个特殊的挑战，他们一直在努力识别和监管药物市场上出现的每种新化合物。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与经典大麻素的药理学不同程度。
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.
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影响因子：
3.5
作者：
Huffman, JW;Zengin, G;Martin, BR
通讯作者：
Martin, BR
使用高分辨率的质谱和质谱滤波来分析合成大麻素，对设计师药物的非目标筛查的影响。
影响因子：
7.4
作者：
Grabenauer M;Krol WL;Wiley JL;Thomas BF
通讯作者：
Thomas BF
影响因子：
3.5
作者：
Dutta, AK;Ryan, W;Razdan, RK
通讯作者：
Razdan, RK
影响因子：
2.7
作者：
HUFFMAN, JW;DAI, D;COMPTON, DR
通讯作者：
COMPTON, DR
影响因子：
7.3
作者：
COMPTON, DR;LITTLE, PJ;RAZDAN, RK
通讯作者：
RAZDAN, RK