Synthesis and evaluation of 4-fluoro-8-substituted-2,3,4,5-tetrahydro-1H-2-benzazapines as selective inhibitors of phenylethanolamine N-methyltransferase versus the α2-adrenoceptor

被引：33

作者：

Grunewald, GL ^{[1
]}

Caldwell, TM ^{[1
]}

Li, QF ^{[1
]}

Criscione, KR ^{[1
]}

机构：

[1] Univ Kansas, Dept Med Chem, Lawrence, KS 66045 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2001年 / 44卷 / 17期

关键词：

D O I：

10.1021/jm010147g

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

A small series of 4-fluoro-8-substituted-2,3,4,5-tetrahydro-1H-2-benzazapines (4-fluoro-THBAs; 12-15) were synthesized and evaluated as inhibitors of phenylethanolamine N-methyltransferase (PNMT; EC 2.1.1.28) and as inhibitors of the binding of clonidine at the alpha (2)-adrenoceptor. 4-Fluoro-THBAs 13-15 displayed selectivity ratios (alpha (2) K-i/PNMT K-i) greater than 75 and 4-fluoro-8-nitro-THBA (13) was found to be one of the most selective inhibitors of PNMT known, with a selectivity ratio of greater than 900. These compounds are also quite lipophilic and according to previous results from this laboratory should be able to penetrate the blood-brain barrier. These 4-fluoro-THBAs represent important leads in the development of new, more selective, CNS-active inhibitors of PNMT.

引用

页码：2849 / 2856

页数：8

共 42 条

[1] Effect of phenylethanolamine N-methyltransferase inhibitor, CGS19281A, on the alpha-2-adrenoceptor function in the hypothalamus of rats in comparison with SKF29661, SKF64139 and yohimbine [J].