Pharmacological Investigations of the Dissociative 'Legal Highs' Diphenidine, Methoxphenidine and Analogues.
Pharmacological Investigations of the Dissociative 'Legal Highs' Diphenidine, Methoxphenidine and Analogues.
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DOI：
10.1371/journal.pone.0157021
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发表时间：
2016
期刊：
影响因子：
3.7
通讯作者：
Adejare A
中科院分区：
文献类型：
--
作者：
Wallach J;Kang H;Colestock T;Morris H;Bortolotto ZA;Collingridge GL;Lodge D;Halberstadt AL;Brandt SD;Adejare A
1,2-二乙基胺（包括lanicemine、lefetamine和remacemide）在一系列治疗领域具有临床相关性，包括疼痛管理、癫痫、神经退行性疾病和抑郁症。最近，1,2-二乙胺以粉末和片剂等多种形式作为“合法兴奋剂”出售。出售这些化合物是为了规避政府管制精神药物的立法。例子包括阿片类药物MT-45和解离剂苯苯胺（DPH）和2-甲氧基苯苯胺（2-MXP）。一些致命和非致命的过量服用与滥用这些化合物有关。与许多“合法兴奋剂”一样，人们对它们的药理知之甚少。为了更好地了解DPH、2-MXP及其3-和4-MeO-异构体和2- cl -苯苯胺（2-Cl-DPH）对46种中枢神经系统受体的影响，包括n -甲基-d -天冬氨酸受体（NMDAR）、5 -羟色胺、多巴胺、去甲肾上腺素、组胺和sigma受体以及5 -羟色胺、多巴胺和去甲肾上腺素的再摄取转运体。测定血清素、去甲肾上腺素和多巴胺转运体的再摄取抑制作用。通过NMDAR诱导的场兴奋性突触后电位（fEPSP）实验，体外建立了NMDAR的拮抗作用。最后，DPH和2-MXP通过脉冲前惊吓抑制实验（PPI）在大鼠中进行研究，以确定它们是否能减少感觉运动门控，这与已知的解离药物如苯环利定（PCP）和氯胺酮观察到的效果相同。结果表明，这些1,2-二乙基乙胺是相对选择性的NMDAR拮抗剂，对多巴胺和去甲肾上腺素的再摄取具有较弱的脱靶抑制作用。DPH和2-MXP显著抑制PPI。DPH的效价高于2-MXP，中位有效剂量（ED50）为9.5 mg/kg，低于其他常见滥用的解离性药物如PCP和氯胺酮的效价。
1,2-Diarylethylamines including lanicemine, lefetamine, and remacemide have clinical relevance in a range of therapeutic areas including pain management, epilepsy, neurodegenerative disease and depression. More recently 1,2-diarylethylamines have been sold as ‘legal highs’ in a number of different forms including powders and tablets. These compounds are sold to circumvent governmental legislation regulating psychoactive drugs. Examples include the opioid MT-45 and the dissociative agents diphenidine (DPH) and 2-methoxy-diphenidine (2-MXP). A number of fatal and non-fatal overdoses have been linked to abuse of these compounds. As with many ‘legal highs’, little is known about their pharmacology. To obtain a better understanding, the effects of DPH, 2-MXP and its 3- and 4-MeO- isomers, and 2-Cl-diphenidine (2-Cl-DPH) were investigated using binding studies at 46 central nervous system receptors including the N-methyl-D-aspartate receptor (NMDAR), serotonin, dopamine, norepinephrine, histamine, and sigma receptors as well as the reuptake transporters for serotonin, dopamine and norepinephrine. Reuptake inhibition potencies were measured at serotonin, norepinephrine and dopamine transporters. NMDAR antagonism was established in vitro using NMDAR-induced field excitatory postsynaptic potential (fEPSP) experiments. Finally, DPH and 2-MXP were investigated using tests of pre-pulse inhibition of startle (PPI) in rats to determine whether they reduce sensorimotor gating, an effect observed with known dissociative drugs such as phencyclidine (PCP) and ketamine. The results suggest that these 1,2-diarylethylamines are relatively selective NMDAR antagonists with weak off-target inhibitory effects on dopamine and norepinephrine reuptake. DPH and 2-MXP significantly inhibited PPI. DPH showed greater potency than 2-MXP, acting with a median effective dose (ED50) of 9.5 mg/kg, which is less potent than values reported for other commonly abused dissociative drugs such as PCP and ketamine.