期刊
JOURNAL OF MEDICINAL CHEMISTRY
卷 52, 期 8, 页码 2384-2392出版社
AMER CHEMICAL SOC
DOI: 10.1021/jm8014553
关键词
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资金
- Spanish Ministerio de Educacion [SAF-2007/ 67008]
- Comunidad Autonoma de Madrid [CAM, S-SAL-2492006]
- Instituto de Salud Carlos III [RD07/0067/0008]
- AGAUR [SGR2005-00390]
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.
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