Synthesis and biological evaluation of nonpeptide mimetics of ω-conotoxin GVIA Original Research Article

A benzothiazole-derived compound (4a) designed to mimic the Cα–Cβ 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 (IC50=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, IC50= 4.1 μM) showed a greater than 25-fold selectivity for the N-type channel.