title: 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.
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 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.
authors.affiliation: Department of Medicinal Chemistry, University of Kansas, Lawrence, Kansas 66045, USA. ggrunewald@ukans.edu
authors.forename: G L
authors.initials: GL
authors.lastname: Grunewald
authors.forename: T M
authors.initials: TM
authors.lastname: Caldwell
authors.forename: Q
authors.initials: Q
authors.lastname: Li
authors.forename: K R
authors.initials: KR
authors.lastname: Criscione
mesh_terms: D000317:Adrenergic alpha-Antagonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D001552:Benzazepines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002540:Cerebral Cortex / Q000378:metabolism; D003000:Clonidine / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D066298:In Vitro Techniques; D008297:Male; D008958:Models, Molecular; D010646:Phentolamine / Q000378:metabolism; D010625:Phenylethanolamine N-Methyltransferase / Q000037:antagonists & inhibitors*; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D018341:Receptors, Adrenergic, alpha-2 / Q000187:drug effects* / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D000317:Adrenergic alpha-Antagonists; D001552:Benzazepines; D004791:Enzyme Inhibitors; D018341:Receptors, Adrenergic, alpha-2; D010625:Phenylethanolamine N-Methyltransferase; D003000:Clonidine; D010646:Phentolamine