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 alpha(2)-adrenoceptor

A small series of 4-fluoro-8-substituted-2,3,4,5-tetrahydro-1H-2-benzazapin es (4-fluoro-THBAs; 12-15) were synthesized and evaluated as inhibitors of phenylethanolamine N-methyltransferase (PNMT; EC 2.1.1.28) and as inhibitor s 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 7 5 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. The se compounds are also quite lipophilic and according to previous results fr om this laboratory should be able to penetrate the blood-brain barrier. The se 4-fluoro-THBAs represent important leads in the development of new, more selective, CNS-active inhibitors of PNMT.