Exploring the active site of phenylethanolamine N-methyltransferase with 1,2,3,4-tetrahydrobenz[h]isoquinoline inhibitors

Bioorg Med Chem. 2007 Feb 1;15(3):1298-310. doi: 10.1016/j.bmc.2006.11.010. Epub 2006 Nov 10.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Binding Sites
  • Crystallography, X-Ray
  • Enzyme Inhibitors / pharmacology*
  • Humans
  • Models, Molecular
  • Molecular Structure
  • Phenylethanolamine N-Methyltransferase / antagonists & inhibitors*
  • Radioligand Assay
  • Receptors, Adrenergic, alpha-2 / metabolism
  • Structure-Activity Relationship
  • Tetrahydroisoquinolines / pharmacology*

Substances

  • Enzyme Inhibitors
  • Receptors, Adrenergic, alpha-2
  • Tetrahydroisoquinolines
  • Phenylethanolamine N-Methyltransferase