Synthesis and biological evaluation of nonpeptide mimetics of co-conotoxin GVIA
- Author(s)
- Baell, JB; Duggan, PJ; Forsyth, SA; Lewis, RJ; Lok, YP; Schroeder, CI;
- Details
- Publication Year 2004-08-01,Volume 12,Issue #15,Page 4025-4037
- Journal Title
- BIOORGANIC & MEDICINAL CHEMISTRY
- Publication Type
- Journal Article
- Abstract
- 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.
- Publisher
- PERGAMON-ELSEVIER SCIENCE LTD
- Keywords
- NEURONAL CALCIUM-CHANNELS; OMEGA-CONOTOXINS; FUNCTIONAL ASSAY; ANALOGS; ANTAGONISTS; MVIIA; DEPROTECTION; ZICONOTIDE; REMOVAL; BLOCKER
- Publisher's Version
- https://doi.org/10.1016/j.bmc.2004.05.040
- Terms of Use/Rights Notice
- Refer to copyright notice on published article.
Creation Date: 2004-08-01 12:00:00