The dopamine, serotonin and norepinephrine releasing activities of a series of methcathinone analogs in male rat brain synaptosomes.
The dopamine, serotonin and norepinephrine releasing activities of a series of methcathinone analogs in male rat brain synaptosomes.
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雄性大鼠脑突触体中一系列甲性苯他酮类似物的多巴胺，5-羟色胺和去甲肾上腺素释放活性。
DOI：
10.1007/s00213-018-5063-9
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发表时间：
2019-03
影响因子：
3.4
通讯作者：
Rothman RB
中科院分区：
文献类型：
--
作者：
Blough BE;Decker AM;Landavazo A;Namjoshi OA;Partilla JS;Baumann MH;Rothman RB
新型合成“浴盐”卡替诺酮继续作为滥用和上瘾的毒品出现在街道上。不同卡西酮产生的主观体验范围表明，一些化合物主要具有多巴胺能活性(可能是刺激物)，而其他化合物主要是5-羟色胺能活性(可能是致病作用)。了解这些化合物的结构活性关系(SARS)将有助于评估未来新结构可能产生的行为效应，并确定潜在的治疗策略以逆转任何增强效应。系统地研究了一系列美卡西酮类似物在多巴胺和5-羟色胺转运体上的活性。芳基上的化合物结构因取代基或苯环被萘或吲哚环取代而发生变化。开发了一种新的高产率合成盐酸美卡西酮的方法，避免了不稳定的游离碱的分离。大鼠脑突触体内神经递质转运体释放活性的测定与以前的报道相同。化合物也被筛选去甲肾上腺素转运体的活性。在多巴胺和5-羟色胺转运体释放试验中，对28个美卡西酮类似物进行了分析和充分表征。2位取代的化合物(邻位)主要是多巴胺能的。在3-位取代的化合物(Meta)被发现多巴胺能要少得多，一些取代基有利于5-羟色胺能活性。在4位取代的化合物(Para)被发现具有更强的5-羟色胺能，二取代化合物和其他大的芳香族基团也是如此。一个例外是氟取代的类似物，它似乎有利于多巴胺转运体。多巴胺能与5-羟色胺能比可以通过选择取代基和芳环上的位置来控制。因此，有可能通过调整它们的结构来调整这些化合物的主观和强化效果。某些取代基，如氟基，倾向于支持多巴胺转运体，而另一些取代基，如三氟甲基，则倾向于5-羟色胺转运体。
Novel synthetic ‘bath salt’ cathinones continue to appear on the street as abused and addictive drugs. The range of subjective experiences produced by different cathinones suggests that some compounds have primarily dopaminergic activity (possible stimulants) while others have primarily serotonergic activity (possible empathogenics). An understanding of the structure activity relationships (SARs) of these compounds will help in assessing the likely behavioral effects of future novel structures, and to define potential therapeutic strategies to reverse any reinforcing effects. A series of methcathinone analogues was systematically studied for their activity at the dopamine and serotonin transporters. Compound structures varied at the aromatic group, either by substituent or by replacement of the phenyl ring with a naphthalene or indole ring. A novel, high yielding synthesis of methcathinone hydrochlorides was developed which avoids isolation of the unstable free bases. Neurotransmitter transporter release activity was determined in rat brain synaptosomes as previously reported. Compounds were also screened for activity at the norepinephrine transporter. Twenty-eight methcathinone analogs were analyzed and fully characterized in dopamine and serotonin transporter release assays. Compounds substituted at the 2-position (ortho) were primarily dopaminergic. Compounds substituted at the 3-position (meta) were found to be much less dopaminergic, with some substituents favoring serotonergic activity. Compounds substituted at the 4position (para) were found to be far more serotonergic, as were disubstituted compounds and other large aromatic groups. One exception was the fluoro substituted analogs which seem to favor the dopamine transporter. The dopaminergic to serotonergic ratio can be manipulated by choice of substituent and location on the aromatic ring. It is therefore likely possible to tweak the subjective and reinforcing effects of these compounds by adjusting their structure. Certain substituents like a fluoro group tend to favor the dopamine transporter, while others like a trifluoromethyl group favor the serotonin transporter.
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影响因子：
--
作者：
Glennon RA;Dukat M
通讯作者：
Dukat M
影响因子：
3.4
作者：
Gatch, Michael B.;Rutledge, Margaret A.;Forster, Michael J.
通讯作者：
Forster, Michael J.
影响因子：
7.3
作者：
Bonano, J. S.;Banks, M. L.;Negus, S. S.
通讯作者：
Negus, S. S.
影响因子：
4.7
作者：
Luethi, Dino;Kolaczynska, Karolina E.;Liechti, Matthias E.
通讯作者：
Liechti, Matthias E.
影响因子：
3.6
作者：
GLENNON, RA;YOUSIF, M;KALIX, P
通讯作者：
KALIX, P