title: Exploring the active site of phenylethanolamine N-methyltransferase: 3-alkyl-7-substituted-1,2,3,4-tetrahydroisoquinoline inhibitors.
abstract: A series of 3-alkyl-7-substituted-1,2,3,4-tetrahydroisoquinolines was synthesized and these compounds were evaluated for their PNMT inhibitory potency and affinity for the alpha2-adrenoceptor. 7-Nitro-, 7-bromo-, 7-aminosulfonyl-, or 7-N-2,2,2-trifluoroethylaminosulfonyl-THIQs that possess a 3-alkyl substituent that is longer than a methyl group showed decreased PNMT inhibitory potency, except for 3-propyl-7-aminosulfonyl-THIQ, which displayed excellent PNMT inhibitory potency. The rank order for selectivity (PNMT vs the alpha2-adrenoceptor) is 3-alkyl-7-aminosulfonyl-THIQs congruent with 3-alkyl-7-N-2,2,2-trifluoroethylaminosulfonyl-THIQs>3-alkyl-7-nitro-THIQs>3-alkyl-7-bromo-THIQs.
authors.affiliation: Department of Medicinal Chemistry, School of Pharmacy, Malott Hall, Room 4060, University of Kansas, 1251 Wescoe Hall Dr., Lawrence, KS 66045-7582, USA.
authors.forename: Gary L
authors.initials: GL
authors.lastname: Grunewald
authors.forename: F Anthony
authors.initials: FA
authors.lastname: Romero
authors.forename: Alex D
authors.initials: AD
authors.lastname: Chieu
authors.forename: Kelcie J
authors.initials: KJ
authors.lastname: Fincham
authors.forename: Seema R
authors.initials: SR
authors.lastname: Bhat
authors.forename: Kevin R
authors.initials: KR
authors.lastname: Criscione
mesh_terms: D001665:Binding Sites; D004791:Enzyme Inhibitors / Q000378:metabolism / Q000494:pharmacology*; D007546:Isoquinolines / Q000378:metabolism / Q000494:pharmacology*; D009682:Magnetic Resonance Spectroscopy; D010625:Phenylethanolamine N-Methyltransferase / Q000037:antagonists & inhibitors*; D011869:Radioligand Assay
chemical_list: D004791:Enzyme Inhibitors; D007546:Isoquinolines; D010625:Phenylethanolamine N-Methyltransferase