Abstract：
Structure-activity studies of 4-substituted-2,5-dimethoxyphenethylamines led to the discovery of 2,5-dimethoxy-4-thiotrifluoromethylphenethylamines, including CYB210010, a potent and long-acting serotonin 5-HT2 receptor agonist. CYB210010 exhibited high agonist potency at 5-HT2A and 5-HT2C receptors, modest selectivity over 5-HT2B, 5-HT1A, 5-HT6, and adrenergic α2A receptors, and lacked activity at monoamine transporters and over 70 other proteins. CYB210010 (0.1-3 mg/kg) elicited a head-twitch response (HTR) and could be administered subchronically at threshold doses without behavioral tolerance. CYB210010 was orally bioavailable in three species, readily and preferentially crossed into the CNS, engaged frontal cortex 5-HT2A receptors, and increased the expression of genes involved in neuroplasticity in the frontal cortex. CYB210010 represents a new tool molecule for investigating the therapeutic potential of 5-HT2 receptor activation. In addition, several other compounds with high 5-HT2A receptor potency, yet with little or no HTR activity, were discovered, providing the groundwork for the development of nonpsychedelic 5-HT2A receptor ligands.
摘要：
4-取代的-2,5-二甲氧基苯乙胺的结构活性研究导致发现了2,5-二甲氧基-4-硫代三氟甲基苯乙胺，包括CYB210010，一种有效的长效5-羟色胺5-HT2受体激动剂。CYB210010对5-HT2A和5-HT2C受体表现出高激动剂效力，对5-HT2B的选择性适中，5-HT1A,5-HT6和肾上腺素能α2A受体，对单胺转运蛋白和70多种其他蛋白质缺乏活性。CYB210010（0.1-3mg/kg）引起头部抽搐反应（HTR），可以在无行为耐受性的阈值剂量下慢性给药。CYB210010在三个物种中具有口服生物可利用性，容易和优先进入中枢神经系统，参与额叶皮质5-HT2A受体，并增加额叶皮质神经可塑性基因的表达。CYB210010代表了用于研究5-HT2受体激活的治疗潜力的新工具分子。此外,其他几种具有高5-HT2A受体效力的化合物，然而，很少或没有HTR活动，被发现,为非迷幻5-HT2A受体配体的开发奠定了基础。
