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

Bioorg Med Chem. 2004 Aug 1;12(15):4025-37. doi: 10.1016/j.bmc.2004.05.040.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Binding, Competitive / drug effects
  • Brain Chemistry
  • Calcium Channel Blockers / chemical synthesis*
  • Calcium Channel Blockers / chemistry
  • Calcium Channel Blockers / pharmacology*
  • Calcium Channels, N-Type / drug effects*
  • Calcium Channels, P-Type / drug effects
  • Calcium Channels, Q-Type / drug effects
  • Drug Design
  • Models, Molecular
  • Molecular Mimicry*
  • Molecular Structure
  • Radioligand Assay
  • Rats
  • Structure-Activity Relationship
  • omega-Conotoxin GVIA / chemistry*
  • omega-Conotoxin GVIA / pharmacology

Substances

  • Calcium Channel Blockers
  • Calcium Channels, N-Type
  • Calcium Channels, P-Type
  • Calcium Channels, Q-Type
  • omega-Conotoxin GVIA