Monohydroxylated metabolites of the K2 synthetic cannabinoid JWH-073 retain intermediate to high cannabinoid 1 receptor (CB1R) affinity and exhibit neutral antagonist to partial agonist activity.
Monohydroxylated metabolites of the K2 synthetic cannabinoid JWH-073 retain intermediate to high cannabinoid 1 receptor (CB1R) affinity and exhibit neutral antagonist to partial agonist activity.
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DOI：
10.1016/j.bcp.2012.01.004
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发表时间：
2012-04-01
影响因子：
5.8
通讯作者：
Prather PL
中科院分区：
文献类型：
--
作者：
Brents LK;Gallus-Zawada A;Radominska-Pandya A;Vasiljevik T;Prisinzano TE;Fantegrossi WE;Moran JH;Prather PL
K2和几种类似的掺有合成大麻素的所谓“熏香产品”被滥用为大麻替代品。我们假设JWH-073（一种在K2中发现的普遍大麻素）的代谢导致了与K2使用相关的毒性。竞争受体结合研究和G-蛋白活化试验（均通过采用小鼠脑匀浆进行）分别用于测定大麻素1受体（CB 1 R）的潜在单羟基化（M1、M3-M5）和单羧基化（M6）代谢物的亲和力和内在活性。令人惊讶的是，M1、M4和M5保留了对CB 1 R的纳摩尔亲和力，而M3显示出微摩尔亲和力，M6不结合CB 1 R。JWH-073表现出与CB 1 R完全激动剂CP-55，940相当的功效，而M1、M3和M5作为CB 1 R部分激动剂，M4表现出很少或没有内在活性。通过Schild分析进行的进一步体外研究显示，M4作为竞争性中性CB 1 R拮抗剂（Kb~ 40 nM）发挥作用。与体外研究一致，M4还通过减弱大麻素诱导的小鼠体温过低在体内表现出CB 1 R拮抗作用。有趣的是，M4不阻断大麻素四分体中的其他测量的激动剂介导的应答（例如，运动抑制、僵硬症或镇痛）。最后，也如体外结果所预测，M1通过诱导小鼠显著体温降低和自发活动抑制而在体内表现出激动剂活性。总之，本研究表明，进一步研究合成大麻素代谢的生理作用是必要的。代谢产生的CB 1 R配体的这种复杂混合物可能导致含JWH-073产品的不良反应特征。
K2 and several similar purported “incense products” spiked with synthetic cannabinoids are abused as cannabis substitutes. We hypothesized that metabolism of JWH-073, a prevalent cannabinoid found in K2, contributes to toxicity associated with K2 use. Competition receptor binding studies and G-protein activation assays, both performed by employing mouse brain homogenates, were used to determine the affinity and intrinsic activity, respectively, of potential monohydroxylated (M1, M3–M5) and monocarboxylated (M6) metabolites at cannabinoid 1 receptors (CB1Rs). Surprisingly, M1, M4 and M5 retain nanomolar affinity for CB1Rs, while M3 displays micromolar affinity and M6 does not bind to CB1Rs. JWH-073 displays equivalent efficacy to that of the CB1R full agonist CP-55,940, while M1, M3, and M5 act as CB1R partial agonists, and M4 shows little or no intrinsic activity. Further in vitro investigation by Schild analysis revealed that M4 acts as a competitive neutral CB1R antagonist (Kb~40nM). In agreement with in vitro studies, M4 also demonstrates CB1R antagonism in vivo by blunting cannabinoid-induced hypothermia in mice. Interestingly, M4 does not block agonist-mediated responses of other measures in the cannabinoid tetrad (e.g., locomotor suppression, catalepsy or analgesia). Finally, also as predicted by in vitro results, M1 exhibits agonist activity in vivo by inducing significant hypothermia and suppression of locomotor activity in mice. In conclusion, the present study indicates that further work examining the physiological effects of synthetic cannabinoid metabolism is warranted. Such a complex mix of metabolically produced CB1R ligands may contribute to the adverse effect profile of JWH-073-containing products.
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