基于 1,3-二氧戊环的 5-HT 受体激动剂的合成及用于中枢神经系统疾病和神经性疼痛的生物学评价。
Synthesis and biological evaluation of 1,3-dioxolane-based 5-HT receptor agonists for CNS disorders and neuropathic pain.
机构信息
Dipartimento di Scienze della Vita, Università degli Studi di Modena e Reggio Emilia, Via Campi 103, 41125 Modena, Italy.
Dipartimento di Farmacia, Università degli Studi di Genova, Viale Benedetto XV 3, 16132 Genova, Italy.
出版信息
Future Med Chem. 2018 Sep 1;10(18):2137-2154. doi: 10.4155/fmc-2018-0107. Epub 2018 Jul 25.
AIM
Targeting 5-HT receptor (5-HTR) as a strategy for CNS disorders and pain control.
METHODOLOGY
A series of 1,3-dioxolane-based 2-heteroaryl-phenoxyethylamines was synthesized by a convergent approach and evaluated at α-adrenoceptors and 5-HTR by binding and functional experiments. Absorption, distribution, metabolism, excretion and toxicity prediction studies were performed to explore the drug-likeness of the compounds.
RESULTS & CONCLUSION: The most promising compound, the pyridin-4-yl derivative, emerged as a potent and selective 5-HTR agonist (pKi = 9.2; pD2 = 8.83; 5-HT/α1 = 135). In vitro it was able to permeate by passive diffusion MDCKII-MDR1 monolayer mimicking the blood-brain barrier and showed promising neuroprotective activity.
目的
将 5-羟色胺受体（5-HTR）作为治疗中枢神经系统疾病和疼痛的靶点。
方法
通过会聚方法合成了一系列基于 1,3-二氧戊环的 2-杂芳基苯氧乙胺，并通过结合和功能实验在 α-肾上腺素能受体和 5-HTR 上进行了评估。进行了吸收、分布、代谢、排泄和毒性预测研究，以探索化合物的类药性。
结果与结论
最有前途的化合物，吡啶-4-基衍生物，作为一种有效的、选择性的 5-HTR 激动剂出现（pKi=9.2；pD2=8.83；5-HT/α1=135）。它在体外能够通过模拟血脑屏障的 MDCKII-MDR1 单层的被动扩散渗透，并且表现出有希望的神经保护活性。
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