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

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Grunewald GL, Seim MR, Regier RC, Criscione KR

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. Epub 2006 Nov 10.

PubMed ID

17126018 [ View in PubMed

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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.

DrugBank Data that Cites this Article

Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
1,2,3,4-Tetrahydro-Isoquinoline-7-Sulfonic Acid Amide	Phenylethanolamine N-methyltransferase	Ki (nM)	280	N/A	N/A	Details
7,8-Dichloro-1,2,3,4-tetrahydroisoquinoline	Phenylethanolamine N-methyltransferase	Ki (nM)	3.1	N/A	N/A	Details