Exploring the active site of phenylethanolamine N-methyltransferase with 1,2,3,4-tetrahydrobenz[h]isoquinoline inhibitors |
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Authors: | Grunewald Gary L Seim Mitchell R Regier Rachel C Criscione Kevin R |
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Institution: | Department of Medicinal Chemistry, University of Kansas, Lawrence, KS 66045, USA. ggrunewald@ku.edu |
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Abstract: | 1,2,3,4-Tetrahydrobenzh]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. |
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