Hruba Lenka, McMahon Lance R
Department of Pharmacology, University of Texas Health Science Center at San Antonio, San Antonio, Texas.
Department of Pharmacology, University of Texas Health Science Center at San Antonio, San Antonio, Texas
J Pharmacol Exp Ther. 2017 Aug;362(2):278-286. doi: 10.1124/jpet.117.240572. Epub 2017 May 22.
Synthetic cannabinoids have been prohibited due to abuse liability and toxicity. Four such synthetic cannabinoids, AM-2201 ([1-(5-fluoropentyl)indol-3-yl]-naphthalen-1-ylmethanone), CP-47,497 (2-[(1R,3S)-3-hydroxycyclohexyl]-5-(2-methyloctan-2-yl)phenol), JWH-122 [(4-methylnaphthalen-1-yl)-(1-pentylindol-3-yl)methanone], and JWH-250 [2-(2-methoxyphenyl)-1-(1-pentylindol-3-yl)ethanone], were tested for their capacity to produce CB receptor-mediated discriminative stimulus effects in two groups of rhesus monkeys. One group ( = 4) discriminated Δ-tetrahydrocannabinol (∆-THC; 0.1 mg/kg i.v.), and a second group ( = 4) discriminated the cannabinoid antagonist rimonabant (1 mg/kg i.v.) while receiving 1 mg/kg/12 hours of ∆-THC. AM-2201, JWH-122, CP-47,497, JWH-250, and ∆-THC increased ∆-THC lever responding. Duration of action was 1-2 hours for AM-2201, JWH-122, and JWH-250 and 4-5 hours for CP-47,497 and ∆-THC. Rimonabant (1 mg/kg) surmountably antagonized the discriminative stimulus effects of all cannabinoid agonists; the magnitude of rightward shift was 10.6-fold for AM-2201, 10.7-fold for JWH-122, 11.0-fold for CP-47,497, and 15.7-fold for JWH-250. The respective pK values were not significantly different: 6.61, 6.65, 6.66, and 6.83. In ∆-THC-treated monkeys discriminating rimonabant, AM-2201 (0.1 and 0.32 mg/kg), JWH-122 (0.32 and 1 mg/kg), JWH-250 (1 and 3.2 mg/kg), and CP-47,497 (0.32, 1, and 3.2 mg/kg) produced not only rate-decreasing effects that were reversed by rimonabant, but also dose-dependent, rightward shifts in the rimonabant discrimination dose-effect function. These results show striking similarity in the CB receptor mechanism mediating the subjective effects of AM-2201, JWH-122, JWH-250, and CP-47,497. For products containing AM-2201 and JWH-122, a short duration of action could lead to more frequent use; moreover, inattention to differences in potency among synthetic cannabinoids could underlie unexpected toxicity. Rapid reversal of effects by intravenous rimonabant has potential value in emergency situations.
由于存在滥用可能性和毒性，合成大麻素已被禁止。对四种此类合成大麻素，即AM - 2201（[1 - (5 - 氟戊基)吲哚 - 3 - 基]-萘 - 1 - 基甲酮）、CP - 47,497（2 - [(1R,3S)-3 - 羟基环己基]-5 - (2 - 甲基辛 - 2 - 基)苯酚）、JWH - 122 [ (4 - 甲基萘 - 1 - 基)-(1 - 戊基吲哚 - 3 - 基)甲酮]和JWH - 250 [2 - (2 - 甲氧基苯基)-1 - (1 - 戊基吲哚 - 3 - 基)乙酮]，在两组恒河猴中测试了它们产生CB受体介导的辨别性刺激效应的能力。一组（n = 4）辨别Δ - 四氢大麻酚（∆ - THC；0.1 mg/kg静脉注射），另一组（n = 4）在接受1 mg/kg/12小时的∆ - THC时辨别大麻素拮抗剂利莫那班（1 mg/kg静脉注射）。AM - 2201、JWH - 122、CP - 47,497、JWH - 250和∆ - THC增加了∆ - THC杠杆反应。AM - 2201、JWH - 122和JWH - 250的作用持续时间为1 - 2小时，CP - 47,497和∆ - THC的作用持续时间为4 - 5小时。利莫那班（1 mg/kg）可有效拮抗所有大麻素激动剂的辨别性刺激效应；向右移位的幅度，AM - 2201为10.6倍，JWH - 122为10.7倍，CP - 47,497为11.0倍，JWH - 250为15.7倍。各自的pK值无显著差异：分别为6.61、6.65、6.66和6.83。在辨别利莫那班的∆ - THC处理的猴子中，AM - 2201（0.1和0.32 mg/kg）、JWH - 122（0.32和1 mg/kg）、JWH - 250（1和3.2 mg/kg）和CP - 47,497（0.32、1和3.2 mg/kg）不仅产生了可被利莫那班逆转的速率降低效应，还使利莫那班辨别剂量 - 效应函数出现剂量依赖性的向右移位。这些结果表明，介导AM - 2201、JWH - 122、JWH - 250和CP - 47,497主观效应的CB受体机制具有显著相似性。对于含有AM - 2201和JWH - 122的产品，作用持续时间短可能导致更频繁使用；此外，忽视合成大麻素之间效力的差异可能是意外毒性的潜在原因。静脉注射利莫那班可迅速逆转效应，在紧急情况下具有潜在价值。
