Kevin Richard C, Anderson Lyndsey, McGregor Iain S, Boyd Rochelle, Manning Jamie J, Glass Michelle, Connor Mark, Banister Samuel D
School of Psychology, Faculty of Science, The University of Sydney, Sydney, NSW, Australia.
Brain and Mind Centre, The University of Sydney, Sydney, NSW, Australia.
Front Pharmacol. 2019 May 29;10:595. doi: 10.3389/fphar.2019.00595. eCollection 2019.
Synthetic cannabinoid receptor agonists (SCRAs) are the largest class of new psychoactive substances (NPS). New examples are detected constantly, and some are associated with a series of adverse effects, including seizures. CUMYL-4CN-BINACA (1-(4-cyanobutyl)--(2-phenylpropan-2-yl)indazole-3-carboxamide) is structurally related to potent, cumylamine-derived SCRAs such as 5F-CUMYL-PINACA, but is unusual due to a terminal aliphatic nitrile group not frequently encountered in SCRAs or pharmaceuticals. We report here that CUMYL-4CN-BINACA is a potent CB receptor agonist ( = 2.6 nM; EC = 0.58 nM) that produces pro-convulsant effects in mice at a lower dose than reported for any SCRA to date (0.3 mg/kg, i.p). Hypothermic and pro-convulsant effects in mice could be reduced or blocked, respectively, by pretreatment with CB receptor antagonist SR141716, pointing to at least partial involvement of CB receptors . Pretreatment with CB2 receptor antagonist AM-630 had no effect on pro-convulsant activity. The pro-convulsant properties and potency of CUMYL-4CN-BINACA may underpin the toxicity associated with this compound in humans.
合成大麻素受体激动剂（SCRAs）是新型精神活性物质（NPS）中最大的一类。新的例子不断被发现，其中一些与一系列不良反应有关，包括癫痫发作。CUMYL-4CN-BINACA（1-(4-氰基丁基)-1-(2-苯基丙-2-基)吲唑-3-甲酰胺）在结构上与强效的、基于苯乙胺的SCRAs如5F-CUMYL-PINACA相关，但因其末端脂肪族腈基在SCRAs或药物中不常见而显得不同寻常。我们在此报告，CUMYL-4CN-BINACA是一种强效的CB受体激动剂（ = 2.6 nM；EC = 0.58 nM），在小鼠中产生惊厥前效应的剂量低于迄今为止报道的任何SCRAs（0.3 mg/kg，腹腔注射）。小鼠的体温过低和惊厥前效应可分别通过CB受体拮抗剂SR141716预处理而降低或阻断，这表明CB受体至少部分参与其中。用CB2受体拮抗剂AM-630预处理对惊厥前活性没有影响。CUMYL-4CN-BINACA的惊厥前特性和效力可能是该化合物在人类中产生毒性的基础。
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