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

被引：49

作者：

Medina, Rocio A. ^{[2
]}

Sallander, Jessica ^{[1
]}

Benhamu, Bellinda ^{[2
]}

Porras, Esther ^{[2
]}

Campillo, Mercedes ^{[1
]}

Pardo, Leonardo ^{[1
]}

Lopez-Rodriguez, Maria L. ^{[2
]}

机构：

[1] Univ Autonoma Barcelona, Lab Med Computac, Unitat Bioestadist, Fac Med, E-08193 Barcelona, Spain

[2] Univ Complutense Madrid, Dept Quim Organ 1, Fac Ciencias Quim, E-28040 Madrid, Spain

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2009年 / 52卷 / 08期

关键词：

PROTEIN-COUPLED RECEPTOR; ADENYLATE-CYCLASE; MOLECULAR-CLONING; AGONIST BINDING; SMOOTH-MUSCLE; HIGH-AFFINITY; FORCE-FIELD; ANTAGONISTS; AGENTS; MODEL;

D O I：

10.1021/jm8014553

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

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-HT1A receptors. The influence of the different structural features in terms of 5-HT7/5-HT1A receptor affinity and selectivity was analyzed by computational simulations of the complexes between compounds I and beta(2)-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-HT1AR (31-fold), and has been characterized as a partial agonist of the human 5-HT7R.

引用

页码：2384 / 2392

页数：9

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