Paper
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.
Published Jul 13, 2001 · G. L. Grunewald, T. Caldwell, Qifang Li
Journal of Medicinal Chemistry
23
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Abstract
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 α2-adrenoceptor. 4-Fluoro-THBAs 13−15 displayed selectivity ratios (α2 Ki/PNMT Ki) 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.
In Vitro Study4-fluoro-8-substituted-2,3,4,5-tetrahydro-1H-2-benzazapines show promising selectivity ratios for phenylethanolamine N-methyltransferase inhibition, offering potential for new CNS-active inhibitors of PNMT.
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