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Pharmacology of Cumyl-Carboxamide Synthetic Cannabinoid New Psychoactive Substances (NPS) CUMYL-BICA, CUMYL-PICA, CUMYL-5F-PICA, CUMYL-5F-PINACA, and Their Analogues
ACS Chemical Neuroscience ( IF 4.1 ) Pub Date : 2017-08-11 00:00:00 , DOI: 10.1021/acschemneuro.7b00267 Mitchell Longworth 1 , Samuel D. Banister 1, 2 , Rochelle Boyd 3 , Richard C. Kevin 4 , Mark Connor 3 , Iain S. McGregor 4 , Michael Kassiou 1
ACS Chemical Neuroscience ( IF 4.1 ) Pub Date : 2017-08-11 00:00:00 , DOI: 10.1021/acschemneuro.7b00267 Mitchell Longworth 1 , Samuel D. Banister 1, 2 , Rochelle Boyd 3 , Richard C. Kevin 4 , Mark Connor 3 , Iain S. McGregor 4 , Michael Kassiou 1
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Synthetic cannabinoids (SC) are the largest class of new psychoactive substances (NPS), and are increasingly associated with serious adverse effects. The majority of SC NPS are 1,3-disubstituted indoles and indazoles featuring a diversity of subunits at the 1- and 3-positions. Most recently, cumyl-derived indole- and indazole-3-carboxamides have been detected by law enforcement agencies and by emergency departments. Herein we describe the synthesis, characterization, and pharmacology of SCs CUMYL-BICA, CUMYL-PICA, CUMYL-5F-PICA, CUMYL-PINACA, CUMYL-5F-PINACA, and related analogues. All cumyl-derived SCs were potent, efficacious agonists at CB1 (EC50 = 0.43–12.3 nM) and CB2 (EC50 = 11.3–122 nM) receptors in a fluorometric assay of membrane potential, with selectivity for CB1 activation (3.1–53 times over CB2). CUMYL-PICA and CUMYL-5F-PICA were evaluated in rats using biotelemetry, and induced hypothermia and bradycardia at doses of 1 mg/kg. Hypothermia was reversed by pretreatment with a CB1, but not CB2, antagonist, confirming that cumyl-derived SCs are cannabimimetic in vivo.
中文翻译：
Cumyl-Carboxamide合成大麻新精神活性物质（NPS）CUMYL-BICA，CUMYL-PICA，CUMYL-5F-PICA，CUMYL-5F-PINACA及其类似物的药理学
合成大麻素（SC）是新型精神活性物质（NPS）的最大类别，并且越来越多地与严重的不良反应联系在一起。SC NPS的大多数是1，3-二取代的吲哚和吲唑，在1和3位具有多种亚基。最近，执法机构和急诊部门发现了枯基衍生的吲哚和吲唑-3-羧酰胺。在本文中，我们描述了SCs CUMYL-BICA，CUMYL-PICA，CUMYL-5F-PICA，CUMYL-PINACA，CUMYL-5F-PINACA及其相关类似物的合成，表征和药理作用。所有枯基衍生的SC在CB 1（EC 50 = 0.43–12.3 nM）和CB 2（EC 50= 11.3–122 nM）受体在膜电位的荧光测定中，具有CB 1活化的选择性（是CB 2的3.1–53倍）。使用生物遥测法在大鼠中评估了CUMYL-PICA和CUMYL-5F-PICA，并以1 mg / kg的剂量诱发了体温过低和心动过缓。通过用CB 1而不是CB 2拮抗剂进行预处理可以逆转体温过低的现象，这证实了枯基衍生的SC在体内是大麻素。
更新日期：2017-08-11
中文翻译：
Cumyl-Carboxamide合成大麻新精神活性物质（NPS）CUMYL-BICA，CUMYL-PICA，CUMYL-5F-PICA，CUMYL-5F-PINACA及其类似物的药理学
合成大麻素（SC）是新型精神活性物质（NPS）的最大类别，并且越来越多地与严重的不良反应联系在一起。SC NPS的大多数是1，3-二取代的吲哚和吲唑，在1和3位具有多种亚基。最近，执法机构和急诊部门发现了枯基衍生的吲哚和吲唑-3-羧酰胺。在本文中，我们描述了SCs CUMYL-BICA，CUMYL-PICA，CUMYL-5F-PICA，CUMYL-PINACA，CUMYL-5F-PINACA及其相关类似物的合成，表征和药理作用。所有枯基衍生的SC在CB 1（EC 50 = 0.43–12.3 nM）和CB 2（EC 50= 11.3–122 nM）受体在膜电位的荧光测定中，具有CB 1活化的选择性（是CB 2的3.1–53倍）。使用生物遥测法在大鼠中评估了CUMYL-PICA和CUMYL-5F-PICA，并以1 mg / kg的剂量诱发了体温过低和心动过缓。通过用CB 1而不是CB 2拮抗剂进行预处理可以逆转体温过低的现象，这证实了枯基衍生的SC在体内是大麻素。
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