title: Exploring the active site of phenylethanolamine N-methyltransferase with 1,2,3,4-tetrahydrobenz[h]isoquinoline inhibitors.
abstract: 1,2,3,4-Tetrahydrobenz[h]isoquinoline (THBQ, 11) is a potent, inhibitor of phenylethanolamine N-methyltransferase (PNMT). Docking studies indicated that the enhanced PNMT inhibitory potency of 11 (hPNMT K(i)=0.49microM) versus 1,2,3,4-tetrahydroisoquinoline (5, hPNMT K(i)=5.8microM) was likely due to hydrophobic interactions with Val53, Met258, Val272, and Val269 in the PNMT active site. These studies also suggested that the addition of substituents to the 7-position of 11 that are capable of forming hydrogen bonds to the enzyme could lead to compounds (14-18) having enhanced PNMT inhibitory potency. However, these compounds are in fact less potent at PNMT than 11. Furthermore, 7-bromo-THBQ (19, hPNMT K(i)=0.22mM), which has a lipophilic 7-substituent that cannot hydrogen bond to the enzyme, is twice as potent at PNMT than 11. This once again illustrates the limitations of docking studies for lead optimization.
authors.affiliation: Department of Medicinal Chemistry, University of Kansas, Lawrence, KS 66045, USA. ggrunewald@ku.edu
authors.forename: Gary L
authors.initials: GL
authors.lastname: Grunewald
authors.forename: Mitchell R
authors.initials: MR
authors.lastname: Seim
authors.forename: Rachel C
authors.initials: RC
authors.lastname: Regier
authors.forename: Kevin R
authors.initials: KR
authors.lastname: Criscione
mesh_terms: D001665:Binding Sites; D018360:Crystallography, X-Ray; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D010625:Phenylethanolamine N-Methyltransferase / Q000037:antagonists & inhibitors*; D011869:Radioligand Assay; D018341:Receptors, Adrenergic, alpha-2 / Q000378:metabolism; D013329:Structure-Activity Relationship; D044005:Tetrahydroisoquinolines / Q000494:pharmacology*
chemical_list: D004791:Enzyme Inhibitors; D018341:Receptors, Adrenergic, alpha-2; D044005:Tetrahydroisoquinolines; D010625:Phenylethanolamine N-Methyltransferase