Synthetic cathinones (SCs) are designer, psychostimulant drugs of abuse that primarily act on monoamine transporters; little is known about their off-target liability. Abuse of pyrrolidine-containing SCs, such as α-PHP, has been linked to clinical features, including tachycardia and hypertension, and psychiatric events, including delusions and memory impairments-effects mimicking deliriant hallucinogens that are acetylcholine muscarinic receptor (MR) antagonists. α-PHP and nine analogs with modifications in the α-carbon side chain length and/or containing a methylenedioxy moiety were screened for activity at each of the five human MRs. Increasing the length of the α-carbon side chain of 1-phenyl-2-(pyrrolidin-1-yl)ethan-1-one analogs from a methyl (α-PPP) to a propyl (α-PVP) group caused a steep increase in affinity at all MR subtypes, and one extra carbon (α-PHP) further enhanced MR affinity; the presence of a methylenedioxy moiety generally hindered this effect. Highest MR affinity was observed with α-PHP at M2Rs-its M2R affinity (Ki = 251 nM) was 302-fold higher than α-PPP's. M2R-cAMP inhibition and β-arrestin recruitment assays showed that α-PHP is an M2R antagonist (Kb = 120 and 502 nM, respectively). Additional experiments showed α-PHP is also an antagonist of M1R-inositol phosphate production (Kb = 1.4 μM). Human toxicology studies report blood concentrations of pyrrolidine-containing SCs, including α-PHP, that reach micromolar levels during intoxication, indicating α-PHP's MR activity might have physiological relevance. As M2Rs and M1Rs are widely expressed in the autonomic and central nervous systems, α-PHP's anticholinergic activity might be relevant to adverse events associated with α-PHP intoxication.

中文翻译：

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精神刺激性合成卡西酮的结构-活性关系研究揭示了α-吡咯烷基己酮对人毒蕈碱型M2受体的纳摩尔拮抗作用。

合成卡西酮（SCs）是主要用于单胺转运蛋白的滥用者的设计，精神刺激药物；他们对脱靶债务的了解很少。含吡咯烷的SC（例如α-PHP）的滥用与临床特征有关，包括心动过速和高血压，以及精神病事件，包括妄想和记忆力减退-模仿妄想致幻剂（乙酰胆碱毒蕈碱受体（MR）拮抗剂）。筛选了α-PHP和九种在α-碳侧链长度上有修饰和/或含有亚甲二氧基部分的类似物在五个人类MR处的活性。将1-苯基-2-（吡咯烷基-1-基）乙烷-1-酮类似物的α-碳侧链长度从甲基（α-PPP）变为丙基（α-PVP）所有MR亚型的亲和力均增加，一种额外的碳（α-PHP）进一步增强了MR亲和力；亚甲二氧基部分的存在通常阻碍了该作用。用α-PHP在M2Rs处观察到最高的MR亲和力，其M2R亲和力（Ki = 251 nM）比α-PPP高302倍。M2R-cAMP抑制和β-arrestin募集试验表明，α-PHP是M2R拮抗剂（分别为Kb = 120和502 nM）。其他实验表明，α-PHP也是M1R-肌醇磷酸生成的拮抗剂（Kb = 1.4μM）。人类毒理学研究报告称，含吡咯烷的SC（包括α-PHP）的血液浓度在中毒时达到微摩尔水平，这表明α-PHP的MR活性可能与生理相关。由于M2R和M1R在自主神经和中枢神经系统中广泛表达，因此α-PHP'