Exploring the active site of phenylethanolamine N-methyltransferase: 3-alkyl-7-substituted-1,2,3,4-tetrahydroisoquinoline inhibitors.
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.
Grunewald
Gary L
GL
Department of Medicinal Chemistry, School of Pharmacy, Malott Hall, Room 4060, University of Kansas, 1251 Wescoe Hall Dr., Lawrence, KS 66045-7582, USA.
Romero
F Anthony
FA
Chieu
Alex D
AD
Fincham
Kelcie J
KJ
Bhat
Seema R
SR
Criscione
Kevin R
KR
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
D004791:Enzyme Inhibitors; D007546:Isoquinolines; D010625:Phenylethanolamine N-Methyltransferase