Exploring the active site of phenylethanolamine N-methyltransferase:: 3-alkyl-7-substituted-1,2,3,4-tetrahydroisoquinoline inhibitors

被引：9

作者：

Grunewald, GL ^{[1
]}

Romero, FA ^{[1
]}

Chieu, AD ^{[1
]}

Fincham, KJ ^{[1
]}

Bhat, SR ^{[1
]}

Criscione, KR ^{[1
]}

机构：

[1] Univ Kansas, Dept Med Chem, Sch Pharm, Lawrence, KS 66045 USA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY | 2005年 / 13卷 / 04期

关键词：

phenylethanolamine N-methyltransferase; enzyme inhibitors; tetrahydroisoquinolines; structure-based design;

D O I：

10.1016/j.bmc.2004.11.015

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

A series of 3 -alkyl-7 -substituted-1,2,3,4-tetrahydroisoquinolines was synthesized and these compounds were evaluated for their PNMT inhibitory potency and affinity for the (alpha(2)-adrenoceptor. 7-Nitro-, 7-bromo-, 7-aminosulfonyl-, or 7-N-2,2,2-trifluoroethylaminosulfonyl-THIQs that possess a 3-alkyl substituent that is longer than a methyl group showed decreased PNMT inhibitory potency, except for 3-propyl-7-aminosulfonyl-THIQ, which displayed excellent PNMT inhibitory potency. The rank order for selectivity (PNMT vs the alpha(2)-adrenoceptor) is 3 -alkyl -7 -aminosulfonyl-THIQs congruent to 3-alkyl-7-N-2,2,2-trifluoroethylaminosulfonyl-THIQs > 3-alkyl-7-nitro-THlQs > 3-alkyl-7-bromo-THIQs. (C) 2004 Elsevier Ltd. All rights reserved.

引用

页码：1261 / 1273

页数：13

共 33 条

[1] CHARACTERIZATION OF AN INVITRO BLOOD-BRAIN-BARRIER MODEL SYSTEM FOR STUDYING DRUG TRANSPORT AND METABOLISM
AUDUS, KL
BORCHARDT, RT
[J]. PHARMACEUTICAL RESEARCH, 1986, 3 (02) : 81 - 87
[2] AXELROD J, 1962, J BIOL CHEM, V237, P1657
[3] BJORN L, 1982, DRUG METAB DISPOS, V10, P700
[4] BURKE WJ, 1988, CENTRAL NERVOUS SYST, P41
[5] Recombinant human phenylethanolamine N-methyltransferase: Overproduction in Escherichia coli, purification, and characterization
Caine, JM
Macreadie, IG
Grunewald, GL
McLeish, MJ
[J]. PROTEIN EXPRESSION AND PURIFICATION, 1996, 8 (02) : 160 - 166
[6] INTRA-MOLECULAR CYCLIZATION OF 2-PHENYLETHYL ISOCYANATES
DAVIES, RV
IDDON, B
SUSCHITZKY, H
[J]. JOURNAL OF THE CHEMICAL SOCIETY-PERKIN TRANSACTIONS 1, 1978, (02): : 180 - 184
[7] FIESER LF, 1967, REAGENTS ORGANIC SYN, V1, P584
[8] GOLDSTEIN M, 1978, PSYCHOPHARMACOLOGY G, P261
[9] SYNTHESIS AND EVALUATION OF 3-SUBSTITUTED ANALOGS OF 1,2,3,4-TETRAHYDROISOQUINOLINE AS INHIBITORS OF PHENYLETHANOLAMINE N-METHYLTRANSFERASE
GRUNEWALD, GL
SALL, DJ
MONN, JA
[J]. JOURNAL OF MEDICINAL CHEMISTRY, 1988, 31 (04) : 824 - 830
[10] Enantiospecific synthesis of 3-fluoromethyl-, 3-hydroxymethyl-, and 3-chloromethyl-1,2,3,4-tetrahydroisoquinolines as selective inhibitors of phenylethanolamine N-methyltransferase versus the α2-adrenoceptor
Grunewald, GL
Caldwell, TM
Li, QF
Dahanukar, VH
McNeil, B
Criscione, KR
[J]. JOURNAL OF MEDICINAL CHEMISTRY, 1999, 42 (21) : 4351 - 4361

← 1 2 3 4 →