ω-Conotoxin GVIA mimetics based on an anthranilamide core: Effect of variation in ammonium side chain lengths and incorporation of fluorine

被引：16

作者：

Andersson, Asa ^{[2
]}

Baell, Jonathan B. ^{[3
]}

Duggan, Peter J. ^{[1
]}

Graham, Janease E. ^{[1
,4
]}

Lewis, Richard J. ^{[2
]}

Lumsden, Natalie G. ^{[2
]}

Tranberg, C. Elisabet ^{[1
]}

Tuck, Kellie L. ^{[4
]}

Yang, Aijun ^{[2
]}

机构：

[1] CSIRO Mol & Hlth Technol, Clayton, Vic 3169, Australia

[2] Univ Queensland, Inst Mol Biosci, St Lucia, Qld 4072, Australia

[3] Walter & Eliza Hall Inst Med Res, Parkville, Vic 3052, Australia

[4] Monash Univ, Sch Chem, Clayton, Vic 3800, Australia

来源：

BIOORGANIC & MEDICINAL CHEMISTRY | 2009年 / 17卷 / 18期

关键词：

Conotoxin; N-type calcium channels; Ca(v)2.2; Channel blockers; Pain; CALCIUM-CHANNEL BLOCKERS; SEVERE CHRONIC PAIN; NONPEPTIDE MIMETICS; INTRATHECAL ZICONOTIDE; BIOLOGICAL EVALUATION; NEUROPATHIC PAIN; REFRACTORY PAIN; DERIVATIVES; DESIGN; HYDROCHLORIDE;

D O I：

10.1016/j.bmc.2009.07.063

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 number of omega-conotoxin GVIA mimetics based on an anthranilamide core were prepared and tested for their affinity for rat brain Ca(v)2.2 channels. Features such as the presence of hydroxyl and fluoro substituents on the tyrosine side chain mimic, the length of the chains on the lysine/arginine side chain mimics and the use of diguanidino and diamino substituents rather than mono-guanidine/mono-amine substitution were examined. The diguanidinylated compounds proved to be the most active and deletion of the hydroxyl substituent had a limited influence on activity. The SAR associated with variation in the lysine/arginine side chain mimics was not strong. The introduction of a fluoro substituent into the tyrosine mimic produced the most active compound prepared in this study (2g), with an EC50 at rat brain Ca(v)2.2 channels of 6 mu M. Crown Copyright (C) 2009 Published by Elsevier Ltd. All rights reserved.

引用

页码：6659 / 6670

页数：12

共 42 条

[1] Synthesis of NTA3-DTDA -: A chelator-lipid that promotes stable binding of His-tagged proteins to membranes [J].

Altin, Joseph G. ;

Banwell, Martin G. ;

Coghlan, Phillip A. ;

Easton, Christopher J. ;

Nairn, Michael R. ;

Offermann, Daniel A. .

AUSTRALIAN JOURNAL OF CHEMISTRY, 2006, 59 (05) :302-306

[2] Synthesis and biological evaluation of nonpeptide mimetics of co-conotoxin GVIA [J].

Baell, JB ;

Duggan, PJ ;

Forsyth, SA ;

Lewis, RJ ;

Lok, YP ;

Schroeder, CI .

BIOORGANIC & MEDICINAL CHEMISTRY, 2004, 12 (15) :4025-4037

[3] ω-conotoxins and approaches to their non-peptide mimetics [J].

Baell, JB ;

Duggan, PJ ;

Lok, YP .

AUSTRALIAN JOURNAL OF CHEMISTRY, 2004, 57 (03) :179-185

[4] Design and synthesis of type-III mimetics of ω-conotoxin GVIA [J].

Baell, JB ;

Forsyth, SA ;

Gable, RW ;

Norton, RS ;

Mulder, RJ .

JOURNAL OF COMPUTER-AIDED MOLECULAR DESIGN, 2001, 15 (12) :1119-1136

[5] Synthesis and biological evaluation of anthranilamide-based non-peptide mimetics of ω-conotoxin GVIA [J].

Baell, Jonathan B. ;

Duggan, Peter J. ;

Forsyth, Stewart A. ;

Lewis, Richard J. ;

Lok, Y. Phei ;

Schroeder, Christina I. ;

Shepherd, Nicholas E. .

TETRAHEDRON, 2006, 62 (31) :7284-7292

[6] Block of voltage-dependent calcium channels by aliphatic monoamines [J].

Beedle, AM ;

Zamponi, GW .

BIOPHYSICAL JOURNAL, 2000, 79 (01) :260-270

[7] 1H-PYRAZOLE-1-CARBOXAMIDINE HYDROCHLORIDE - AN ATTRACTIVE REAGENT FOR GUANYLATION OF AMINES AND ITS APPLICATION TO PEPTIDE-SYNTHESIS [J].

BERNATOWICZ, MS ;

WU, YL ;

MATSUEDA, GR .

JOURNAL OF ORGANIC CHEMISTRY, 1992, 57 (08) :2497-2502

[8] Current and emerging targets to treat neuropathic pain [J].

Butera, John A. .

JOURNAL OF MEDICINAL CHEMISTRY, 2007, 50 (11) :2543-2546

[9] In silico prediction of blood-brain barrier permeation [J].

Clark, DE .

DRUG DISCOVERY TODAY, 2003, 8 (20) :927-933

[10] Synthesis and Cav2.2 binding data for non-peptide mimetics of ω-conotoxin GVIA based on a 5-amino-anthranilamide core [J].

Duggan, Peter J. ;

Faber, Jonathan M. ;

Graham, Janease E. ;

Lewis, Richard J. ;

Lumsden, Natalie G. ;

Tuck, Kellie L. .

AUSTRALIAN JOURNAL OF CHEMISTRY, 2008, 61 (01) :11-15

← 1 2 3 4 5 →