Synthesis and biological evaluation of nonpeptide mimetics of co-conotoxin GVIA
Synthesis and biological evaluation of nonpeptide mimetics of co-conotoxin GVIA
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DOI：
10.1016/j.bmc.2004.05.040
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发表时间：
2004-08-01
影响因子：
3.5
通讯作者：
Schroeder, CI
中科院分区：
文献类型：
--
作者：
Baell, JB;Duggan, PJ;Schroeder, CI
合成了一种苯并噻唑衍生的化合物（4a），旨在模拟omega- concontoxin GVIA中Lys2、TyrI3和Arg17的c - α -c - β键载体和末端功能，以及每个侧链模拟物被系统截断或消除的类似物（4b-d）。测定了这些化合物对大鼠脑n型和P/ q型电压门控钙通道（VGCCs）的亲和力。在n型通道亲和性和选择性方面，其中两个化合物（4a和4d）被发现是非常有前途的，第一代omega- concontoxin的模拟物。完全功能化的模拟物（4a）对n型VGCCs的PM结合亲和力较低（IC50 = 1.9 muM），对该通道亚型的选择性比P/ q型VGCCs高20倍，而胍型侧链被截断回胺的模拟物（4d, IC50 = 4.1 muM）对n型通道的选择性高于25倍。(C) 2004 Elsevier Ltd.版权所有。
A benzothiazole-derived compound (4a) designed to mimic the C-alpha-C-beta bond vectors and terminal functionalities of Lys2, TyrI3 and Arg17 in omega-conotoxin GVIA was synthesised, together with analogues (4b-d), which had each side-chain mimic systematically truncated or eliminated. The affinity of these compounds for rat brain N-type and P/Q-type voltage gated calcium channels (VGCCs) was determined. In terms of N-type channel affinity and selectivity, two of these compounds (4a and 4d) were found to be highly promising, first generation mimetics of omega-conotoxin. The fully functionalised mimetic (4a) showed low PM binding affinity to N-type VGCCs (IC50 = 1.9 muM) and greater than 20-fold selectivity for this channel sub-type over P/Q-type VGCCs, whereas the mimetic in which the guanidine-type side chain was truncated back to an amine (4d, IC50 = 4.1 muM) showed a greater than 25-fold selectivity for the N-type channel. (C) 2004 Elsevier Ltd. All rights reserved.