期刊
CHEMMEDCHEM
卷 6, 期 6, 页码 1024-1040出版社
WILEY-V C H VERLAG GMBH
DOI: 10.1002/cmdc.201100010
关键词
catechol; D-1-selective agonists; dopamine; drug design; hydrogen bonds
资金
- NIH [MH42705, GM085604, MH60397]
- AFPE
A novel class of isochroman dopamine analogues, originally reported by Abbott Laboratories, have > 100-fold selectivity for D-1-like over D-2-like receptors. We synthesized a parallel series of chroman compounds and showed that repositioning the oxygen atom in the heterocyclic ring decreases potency and confers D-2-like receptor selectivity to these compounds. In silico modeling supports the hypothesis that the altered pharmacology for the chroman series is due to potential intramolecular hydrogen bonding between the oxygen in the chroman ring and the meta-hydroxy group of the catechol moiety. This interaction realigns the catechol hydroxy groups and disrupts key interactions between these ligands and critical serine residues in TM5 of the D-1-like receptors. This hypothesis was tested by the synthesis and pharmacological evaluation of a parallel series of carbocyclic compounds. Our results suggest that if the potential for intramolecular hydrogen bonding is removed, D-1-like receptor potency and selectivity are restored.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据