Quantitative structure-activity relationship analysis of the pharmacology of para-substituted methcathinone analogues
Quantitative structure-activity relationship analysis of the pharmacology of para-substituted methcathinone analogues
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DOI：
10.1111/bph.13030
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发表时间：
2015-05-01
影响因子：
7.3
通讯作者：
Negus, S. S.
中科院分区：
文献类型：
--
作者：
Bonano, J. S.;Banks, M. L.;Negus, S. S.
甲卡西酮（Methcathinone，MCAT）是一种有效的单胺类化合物，也是包括甲氧麻黄酮（4-CH 3 MCAT）在内的新型滥用药物的母体化合物。本研究检查了MCAT和6种对位取代MCAT类似物的定量构效关系（QSAR）：（a）通过多巴胺和5-羟色胺转运蛋白（分别为DAT和SERT）促进单胺释放的体外效力，和（B）颅内自我刺激（ICSS）的体内调节，ICSS是一种用于评价滥用可能性的行为程序。神经化学和行为效应与帕拉取代基的空间（E-s）、电子（sigma（p））和亲脂（（p））参数相关。实验方法对于神经化学研究，在大鼠脑突触体中评估通过DAT和SERT释放单胺的药物效应。对于行为学研究，药物的影响进行了测试，在男性Sprague-Dawley大鼠植入电极靶向内侧前脑束和训练，以按下电brain stimulation.Key ResultsMCAT和所有6个对位取代的类似物增加单胺释放通过DAT和SERT和剂量和时间依赖性调制ICSS。DAT与SERT的体外选择性与产生滥用相关ICSS易化的体内功效相关。此外，E-S值的帕拉取代基相关的DAT与SERT和ICSS facilitation.Conclusions和ImplicationsSelectivity DAT与SERTin体外的选择性的选择性是一个关键的决定因素，滥用相关的ICSS便利这些MCAT类似物，和立体方面的MCAT支架的帕拉取代基（由E-S表示）是这种选择性的关键决定因素。
Background and PurposeMethcathinone (MCAT) is a potent monoamine releaser and parent compound to emerging drugs of abuse including mephedrone (4-CH3 MCAT), the para-methyl analogue of MCAT. This study examined quantitative structure-activity relationships (QSAR) for MCAT and six para-substituted MCAT analogues on (a) in vitro potency to promote monoamine release via dopamine and serotonin transporters (DAT and SERT, respectively), and (b) in vivo modulation of intracranial self-stimulation (ICSS), a behavioural procedure used to evaluate abuse potential. Neurochemical and behavioural effects were correlated with steric (E-s), electronic (sigma(p)) and lipophilic ((p)) parameters of the para substituents.Experimental ApproachFor neurochemical studies, drug effects on monoamine release through DAT and SERT were evaluated in rat brain synaptosomes. For behavioural studies, drug effects were tested in male Sprague-Dawley rats implanted with electrodes targeting the medial forebrain bundle and trained to lever-press for electrical brain stimulation.Key ResultsMCAT and all six para-substituted analogues increased monoamine release via DAT and SERT and dose- and time-dependently modulated ICSS. In vitro selectivity for DAT versus SERT correlated with in vivo efficacy to produce abuse-related ICSS facilitation. In addition, the E-s values of the para substituents correlated with both selectivity for DAT versus SERT and magnitude of ICSS facilitation.Conclusions and ImplicationsSelectivity for DAT versus SERTin vitro is a key determinant of abuse-related ICSS facilitation by these MCAT analogues, and steric aspects of the para substituent of the MCAT scaffold (indicated by E-s) are key determinants of this selectivity.