title: 3-hydroxymethyl-7-(N-substituted aminosulfonyl)-1,2,3,4-tetrahydroisoquinoline inhibitors of phenylethanolamine N-methyltransferase that display remarkable potency and selectivity.
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).
authors.affiliation: Department of Medicinal Chemistry, University of Kansas, Lawrence, Kansas 66045, USA. ggrunewald@ku.edu
authors.forename: Gary L
authors.initials: GL
authors.lastname: Grunewald
authors.forename: F Anthony
authors.initials: FA
authors.lastname: Romero
authors.forename: Kevin R
authors.initials: KR
authors.lastname: Criscione
mesh_terms: D000818:Animals; D001665:Binding Sites; D001671:Biochemistry / Q000379:methods; D004353:Drug Evaluation, Preclinical / Q000379:methods; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D008297:Male; D008958:Models, Molecular; D010625:Phenylethanolamine N-Methyltransferase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011487:Protein Conformation; D051381:Rats; D017207:Rats, Sprague-Dawley; D018341:Receptors, Adrenergic, alpha-2 / Q000378:metabolism; D012680:Sensitivity and Specificity; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000737:chemistry / Q000494:pharmacology; D044005:Tetrahydroisoquinolines / Q000737:chemistry / Q000494:pharmacology
chemical_list: C119478:7-aminosulfonyl-3-hydroxymethyl-1,2,3,4-tetrahydroisoquinoline; D004791:Enzyme Inhibitors; D018341:Receptors, Adrenergic, alpha-2; D013449:Sulfonamides; D044005:Tetrahydroisoquinolines; D010625:Phenylethanolamine N-Methyltransferase