Drug Discovery Program, Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, University of Illinois at Chicago, Chicago, IL, 60612, United States.
National Institute of Mental Health Psychoactive Drug Screening Program, and Department of Pharmacology and Division of Chemical Biology and Medicinal Chemistry, University of North Carolina Chapel Hill Medical School, Chapel Hill, NC, 27599, United States.
Eur J Med Chem. 2019 Nov 15;182:111626. doi: 10.1016/j.ejmech.2019.111626. Epub 2019 Aug 14.
A new series of fluorinated 5-HT agonists were designed and synthesized on the basis of our previous work on 2-phenylcyclopropylmethylamines as a potential approach for the treatment of central nervous system disorders. Key fluorinated cyclopropane moieties were constructed through transition metal catalyzed [2 + 1]-cycloaddition of aromatic vinyl fluorides, and the absolute stereochemistry of the representative compound (-)-21a was established. Functional activity measuring calcium flux at 5-HT receptors reveals high potency for compounds (+)-21a-d. In particular, (+)-21b had no detectable 5-HT agonism and displayed reasonable selectivity against 5-HT. Molecular docking studies were further performed to explain the compounds' possible binding poses to the 5-HT receptor.
基于我们之前在 2-苯环丙基甲胺作为治疗中枢神经系统疾病的潜在方法方面的工作，设计并合成了一系列新型氟化 5-HT 激动剂。关键的氟化环丙烷部分是通过过渡金属催化的芳基乙烯基氟化物的[2+1]-环加成反应构建的，代表性化合物（-）-21a 的绝对立体化学结构也已确定。通过测量 5-HT 受体的钙流来测定功能活性，结果表明这些化合物具有很高的效力。特别是，（+）-21b 对 5-HT 没有检测到激动作用，并且对 5-HT 具有合理的选择性。进一步进行了分子对接研究，以解释这些化合物与 5-HT 受体可能的结合构象。
