Kaur Harpreet, Karabulut Sedat, Gauld James W, Fagot Stephen A, Holloway Kalee N, Shaw Hannah E, Fantegrossi William E
Pharmala Biotech, Toronto, Canada.
Department of Chemistry and Biochemistry, University of Windsor, Windsor, Ontario, Canada.
Psychedelic Med (New Rochelle). 2023 Sep 13;1(3):166-185. doi: 10.1089/psymed.2023.0023. eCollection 2023 Sep.
Autism spectrum disorder (ASD) encompasses a range of neurodevelopmental syndromes diagnostically characterized by deficits in social communication and social interaction and repetitive, inflexible patterns of behaviors, interests, and thoughts. ASD affects people worldwide, irrespective of race, ethnicity, or socio-economic status, with debilitating effects on employment and interpersonal relationships. Though the atypical antipsychotics aripiprazole and risperidone are approved to treat irritability associated with ASD, these drugs may elicit treatment-limiting adverse effects, such as suicidal ideation, sedation, diarrhea, loss of appetite, dizziness, and weight gain. However, there are no approved pharmacotherapeutics for global symptoms of ASD, and better treatments are needed. Drugs with pro-social effects, such as 3,4-methylenedioxymethamphetamine (MDMA) and its analogues, may be beneficial here, as social anxiety and social avoidance are major complications of ASD that adversely impact the quality of life for sufferers and caregivers. This review describes the complex pharmacology of methylenedioxy amphetamine analogues (hereafter referred to as MDXX drugs), focusing on MDMA and 3,4-methylenedioxy-N-methyl-α-ethylphenylethylamine (MBDB) and how they may help treat ASD. Specifically, we address the roles of various drug-binding sites, metabolic enzymes, and chemical structure-activity relationships that mediate these substances' pharmacological and toxicological effects. Throughout the review, we emphasize the distinct profiles of individual stereoisomers of the MDXX drugs and how combining these enantiomers as racemic mixtures may explain the complexity of drug effects on behavior and physiology. We propose that the MDXX drugs represent a fruitful chemical space for developing clinically effective and relatively safer molecules and formulations for treating ASD.
自闭症谱系障碍（ASD）涵盖一系列神经发育综合征，其诊断特征为社交沟通和社交互动缺陷以及行为、兴趣和思维的重复、刻板模式。ASD影响着世界各地的人们，不分种族、民族或社会经济地位，对就业和人际关系产生不利影响。尽管非典型抗精神病药物阿立哌唑和利培酮被批准用于治疗与ASD相关的易怒情绪，但这些药物可能会引发限制治疗的不良反应，如自杀念头、镇静、腹泻、食欲不振、头晕和体重增加。然而，目前尚无获批用于治疗ASD整体症状的药物疗法，因此需要更好的治疗方法。具有亲社会效应的药物，如3,4-亚甲基二氧基甲基苯丙胺（摇头丸）及其类似物，可能在此处发挥作用，因为社交焦虑和社交回避是ASD的主要并发症，会对患者及其照顾者的生活质量产生不利影响。本综述描述了亚甲基二氧基苯丙胺类似物（以下简称MDXX药物）的复杂药理学，重点关注摇头丸和3,4-亚甲基二氧基-N-甲基-α-乙基苯乙胺（MBDB）以及它们如何帮助治疗ASD。具体而言，我们探讨了各种药物结合位点、代谢酶以及介导这些物质药理和毒理作用的化学结构-活性关系的作用。在整个综述中，我们强调了MDXX药物各个立体异构体的独特特征，以及将这些对映体作为外消旋混合物组合起来如何解释药物对行为和生理影响的复杂性。我们认为，MDXX药物代表了一个富有成果的化学领域，可用于开发治疗ASD的临床有效且相对安全的分子和制剂。
