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 = 0.49 μM) versus 1,2,3,4-tetrahydroisoquinoline ( 5, hPNMT K i = 5.8 μM) 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 = 0.22 mM), 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.