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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

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journal contribution
posted on 13.07.2001, 00:00 by Gary L. Grunewald, Timothy M. Caldwell, Qifang Li, Kevin R. Criscione
A small series of 4-fluoro-8-substituted-2,3,4,5-tetrahydro-1H-2-benzazapines (4-fluoro-THBAs; 1215) were synthesized and evaluated as inhibitors of phenylethanolamine N-methyltransferase (PNMT; EC and as inhibitors of the binding of clonidine at the α2-adrenoceptor. 4-Fluoro-THBAs 1315 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.