کد مقاله کد نشریه سال انتشار مقاله انگلیسی نسخه تمام متن
1364885 981548 2007 13 صفحه PDF دانلود رایگان
عنوان انگلیسی مقاله ISI
Exploring the active site of phenylethanolamine N-methyltransferase with 1,2,3,4-tetrahydrobenz[h]isoquinoline inhibitors
موضوعات مرتبط
مهندسی و علوم پایه شیمی شیمی آلی
پیش نمایش صفحه اول مقاله
Exploring the active site of phenylethanolamine N-methyltransferase with 1,2,3,4-tetrahydrobenz[h]isoquinoline inhibitors
چکیده انگلیسی

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 Ki = 0.49 μM) versus 1,2,3,4-tetrahydroisoquinoline (5, hPNMT Ki = 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 Ki = 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.

A series of 7-substituted-1,2,3,4-tetrahydrobenz[h]isoquinolines were synthesized and examined as potential inhibitors of phenylethanolamine N-methyltransferase (PNMT), the enzyme responsible for the conversion of norepinephrine to epinephrine.Figure optionsDownload as PowerPoint slide

ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Bioorganic & Medicinal Chemistry - Volume 15, Issue 3, 1 February 2007, Pages 1298–1310
نویسندگان
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