Synthesis of New Serotonin 5-HT7 Receptor Ligands. Determinants of 5-HT7/5-HT1A Receptor Selectivity

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• 作者：Roco A. Medina ; Jessica Sallander ; Bellinda Benham ; Esther Porras ; Mercedes Campillo ; Leonardo Pardo ; Mara L. Lpez-Rodrguez
• 刊名：Journal of Medicinal Chemistry
• 出版年：2009
• 出版时间：April 23, 2009
• 年：2009
• 卷：52
• 期：8
• 页码：2384-2392
• 全文大小：267K
• 年卷期：v.52,no.8(April 23, 2009)
• ISSN：1520-4804

文摘

We report the synthesis of a new set of compounds of general structure I (1−20) with structural modifications in the pharmacophoric elements of the previously reported lead UCM-5600. The new derivatives have been evaluated for binding affinity at 5-HT₇ and 5-HT_1A receptors. The influence of the different structural features in terms of 5-HT₇/5-HT_1A receptor affinity and selectivity was analyzed by computational simulations of the complexes between compounds I and β₂-based 3-D models of these receptors. Compound 18 (HYD₁ = 1,3-dihydro-2H-indol-2-one; spacer = −(CH₂)₄−; HYD₂ + HYD₃ = 3,4-dihydroisoquinolin-2(1H)-yl) exhibits high 5-HT₇R affinity (K_i = 7 nM) and selectivity over the 5-HT_1AR (31-fold), and has been characterized as a partial agonist of the human 5-HT₇R.