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.
Publication types
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Comparative Study
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Adrenergic alpha-Antagonists / chemical synthesis*
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Adrenergic alpha-Antagonists / chemistry
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Adrenergic alpha-Antagonists / pharmacology
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Animals
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Benzazepines / chemical synthesis*
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Benzazepines / chemistry
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Benzazepines / pharmacology
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Cerebral Cortex / metabolism
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Clonidine / metabolism
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Enzyme Inhibitors / chemical synthesis*
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Enzyme Inhibitors / chemistry
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Enzyme Inhibitors / pharmacology
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In Vitro Techniques
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Male
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Models, Molecular
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Phentolamine / metabolism
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Phenylethanolamine N-Methyltransferase / antagonists & inhibitors*
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Radioligand Assay
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Rats
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Rats, Sprague-Dawley
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Receptors, Adrenergic, alpha-2 / drug effects*
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Receptors, Adrenergic, alpha-2 / metabolism
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Structure-Activity Relationship
Substances
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Adrenergic alpha-Antagonists
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Benzazepines
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Enzyme Inhibitors
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Receptors, Adrenergic, alpha-2
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Phenylethanolamine N-Methyltransferase
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Clonidine
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Phentolamine