Pharmacology of Valinate and tert-Leucinate Synthetic Cannabinoids 5F-AMBICA, 5F-AMB, 5F-ADB, AMB-FUBINACA, MDMB-FUBINACA, MDMB-CHMICA, and Their Analogues
Pharmacology of Valinate and tert-Leucinate Synthetic Cannabinoids 5F-AMBICA, 5F-AMB, 5F-ADB, AMB-FUBINACA, MDMB-FUBINACA, MDMB-CHMICA, and Their Analogues
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DOI：
10.1021/acschemneuro.6b00137
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发表时间：
2016-09-01
影响因子：
5
通讯作者：
Kassiou, Michael
中科院分区：
文献类型：
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作者：
Banister, Samuel D.;Longworth, Mitchell;Kassiou, Michael
具有L-缬氨酸酯或L-叔亮氨酸酯侧基的吲哚和吲唑合成大麻素（SC）最近成为流行的娱乐性药物，它们的使用与严重的不良健康影响有关。由于这些化合物的药理学数据有限，合成了5 F-AMBICA、5 F-AMB、5 F-ADB、AMB-FUBINACA、MDMB-FUBINACA、MDMB-CHMICA及其类似物，并在体外和体内评估了大麻模拟活性。在膜电位的荧光测定中，所有SC均作为CB 1（EC 50 = 0.45-36 nM）和CB 2（EC 50 = 4.6-128 nM）受体的强效、高效激动剂，通常优先激活CB 1。在大鼠体内使用生物遥测技术证明了两种在人类中具有确认毒性的流行化合物SF-AMB和MDMB-FUBINACA的大麻模拟特性。心动过缓和低体温由0.1-1 mg/kg剂量的5 F-AMB和MDMB-FUBINACA（对于5 F-AMB为3 mg/kg）诱导，MDMB-FUBINACA显示出我们实验室中记录的任何SC的最显著的低体温反应（在0.3 mg/kg下>3 ℃）。通过用CB而不是CB拮抗剂预处理，证明了5 F-AMB和MDMB-FUBINACA的低温恢复，与CB 1介导的体内效应一致。体外和体内数据表明，这些SC作为高度有效的CB受体激动剂，具有比Delta（9）-THC和早期几代SC更大的效力。
Indole and indazole synthetic cannabinoids (SCs) featuring L-valinate or L-tert-leucinate pendant group have recently emerged as prevalent recreational drugs, and their use has been associated with serious adverse health effects. Due to the limited pharmacological data available for these compounds, 5F-AMBICA, 5F-AMB, 5F-ADB, AMB-FUBINACA, MDMB-FUBINACA, MDMB-CHMICA, and their analogues were synthesized and assessed for cannabimimetic activity in vitro and in vivo. All SCs acted as potent, highly efficacious agonists at CB, (EC50 = 0.45-36 nM) and CB2 (EC50 = 4.6-128 nM) receptors in a fluorometric assay of membrane potential, with a general preference for CB1, activation. The cannabimimetic properties of two prevalent compounds with confirmed toxicity in humans, SF-AMB and MDMB-FUBINACA, were demonstrated in vivo using biotelemetry in rats. Bradycardia and hypothermia were induced by 5F-AMB and MDMB-FUBINACA doses of 0.1-1 mg/kg (and 3 mg/kg for 5F-AMB), with MDMB-FUBINACA showing the most dramatic hypothermic response recorded in our laboratory for any SC (>3 degrees C at 0.3 mg/kg). Reversal of hypothermia by pretreatment with a CB but not CB, antagonist was demonstrated for 5F-AMB and MDMB-FUBINACA, consistent with CB1-mediated effects in vivo. The in vitro and in vivo data indicate that these SCs act as highly efficacious CB receptor agonists with greater potency than Delta(9)-THC and earlier generations of SCs.