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Synthesis and biological evaluation of nonpeptide mimetics of omega-conotoxin GVIA.

Abstract：

:A benzothiazole-derived compound (4a) designed to mimic the C(alpha)-C(beta) bond vectors and terminal functionalities of Lys2, Tyr13 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 microM binding affinity to N-type VGCCs (IC(50)=1.9 microM) 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, IC(50)= 4.1 microM) showed a greater than 25-fold selectivity for the N-type channel.

journal_name

Bioorg Med Chem

journal_title

Bioorganic & medicinal chemistry

authors

Baell JB,Duggan PJ,Forsyth SA,Lewis RJ,Lok YP,Schroeder CI

doi

10.1016/j.bmc.2004.05.040

subject

Has Abstract

pub_date

2004-08-01 00:00:00

pages

4025-37

issue

15

eissn

0968-0896

issn

1464-3391

pii

S0968089604004158

journal_volume

12

pub_type

杂志文章

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