Abstract
Six 3-hydroxymethyl-7-(N-substituted aminosulfonyl)-1,2,3,4-tetrahydroisoquinolines (16-21) were synthesized and evaluated for their phenylethanolamine N-methyltransferase (PNMT) inhibitory potency and affinity for the alpha(2)-adrenoceptor. The addition of nonpolar substituents to the sulfonamide nitrogen of 9 (3-CH(2)OH-7-SO(2)NH(2)-THIQ) led to inhibitors (16-21) that have high PNMT inhibitory potency and high selectivity, and most of these (16-21) are predicted, on the basis of their calculated log P values, to be able to penetrate the blood-brain barrier. Compounds N-trifluoroethyl sulfonamide 20 (PNMT K(i) = 23 nM) and N-trifluoropropyl sulfonamide 21 (PNMT K(i) = 28 nM) are twice as potent at inhibiting PNMT compared to 9 and display excellent selectivity (alpha(2) K(i)/PNMT K(i) > or = 15,000).
Publication types
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Research Support, U.S. Gov't, Non-P.H.S.
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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Binding Sites
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Biochemistry / methods
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Drug Evaluation, Preclinical / methods
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Enzyme Inhibitors / chemistry*
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Enzyme Inhibitors / metabolism
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Enzyme Inhibitors / pharmacology*
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Humans
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Hydrophobic and Hydrophilic Interactions
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Male
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Models, Molecular
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Phenylethanolamine N-Methyltransferase / antagonists & inhibitors*
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Phenylethanolamine N-Methyltransferase / metabolism
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Protein Conformation
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Rats
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Rats, Sprague-Dawley
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Receptors, Adrenergic, alpha-2 / metabolism
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Sensitivity and Specificity
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Structure-Activity Relationship
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Sulfonamides / chemistry
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Sulfonamides / pharmacology
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Tetrahydroisoquinolines / chemistry
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Tetrahydroisoquinolines / pharmacology
Substances
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7-aminosulfonyl-3-hydroxymethyl-1,2,3,4-tetrahydroisoquinoline
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Enzyme Inhibitors
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Receptors, Adrenergic, alpha-2
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Sulfonamides
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Tetrahydroisoquinolines
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Phenylethanolamine N-Methyltransferase