Dipartimento di Farmacia-Scienze del Farmaco, Università degli Studi di Bari Aldo Moro, Via Orabona 4, 70125 Bari, Italy.
Institute of Pharmaceutical Chemistry, Goethe-University, Max-von-Laue-Str. 9, 60438 Frankfurt am Main, Germany.
Molecules. 2022 Feb 15;27(4):1297. doi: 10.3390/molecules27041297.
Long-chain arylpiperazine scaffold is a versatile template to design central nervous system (CNS) drugs that target serotonin and dopamine receptors. Here we describe the synthesis and biological evaluation of ten new arylpiperazine derivatives designed to obtain an affinity profile at serotonin 5-HT, 5-HT, 5-HT receptor, and dopamine D receptor of prospective drugs to treat the core symptoms of autism spectrum disorder (ASD) or psychosis. Besides the structural features required for affinity at the target receptors, the new compounds incorporated structural fragments with antioxidant properties to counteract oxidative stress connected with ASD and psychosis. All the new compounds showed CNS MultiParameter Optimization score predictive of desirable ADMET properties and cross the blood-brain barrier. We identified compound that combines an affinity profile compatible with antipsychotic activity (5-HT = 41.5 nM, 5-HT = 315 nM, 5-HT = 42.5 nM, D = 300 nM), and compound that has an affinity profile consistent with studies in the context of ASD (5-HT = 23.9 nM, 5-HT = 39.4 nM, 5-HT = 45.0 nM). Both compounds also had antioxidant properties. All compounds showed low in vitro metabolic stability, the only exception being compound , which might be suitable for studies in vivo.
长链芳基哌嗪骨架是设计靶向 5-羟色胺（5-HT）和多巴胺受体的中枢神经系统（CNS）药物的多功能模板。在这里，我们描述了十个新的芳基哌嗪衍生物的合成和生物学评价，这些衍生物旨在获得对治疗自闭症谱系障碍（ASD）或精神病核心症状的潜在药物的 5-HT 受体、5-HT 受体和多巴胺 D 受体的亲和力谱。除了目标受体亲和力所需的结构特征外，新化合物还包含具有抗氧化特性的结构片段，以抵消与 ASD 和精神病相关的氧化应激。所有新化合物均显示出 CNS 多参数优化评分，预示着理想的 ADMET 特性，并能穿越血脑屏障。我们鉴定出了一种具有抗精神病活性（5-HT = 41.5 nM，5-HT = 315 nM，5-HT = 42.5 nM，D = 300 nM）亲和力谱的化合物 ，以及一种具有与 ASD 背景下研究一致的亲和力谱的化合物 （5-HT = 23.9 nM，5-HT = 39.4 nM，5-HT = 45.0 nM）。这两种化合物都具有抗氧化特性。所有化合物在体外代谢稳定性都较低，唯一的例外是化合物 ，这可能适合体内研究。
