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

Abstract A benzothiazole-derived compound ( 4a ) designed to mimic the C α –C β bond vectors and terminal functionalities of Lys2, Tyr13 and Arg17 in ω-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 ω-conotoxin. The fully functionalised mimetic ( 4a ) showed low μM binding affinity to N-type VGCCs (IC 50 =1.9 μM) 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 μM) showed a greater than 25-fold selectivity for the N-type channel.