Alkyne-Bridged Alpha-Conotoxin Vc1.1 Potently Reverses Mechanical Allodynia In Neuropathic Pain Models

Several Conus-derived venom peptides are promising lead compounds for the management of neuropathic pain, with alpha-conotoxins being of particular interest. Modification of the interlocked disulfide framework of alpha-conotoxin Vc1.1 has been achieved using on-resin alkyne metathesis. Although introduction of a metabolically stable alkyne motif significantly disrupts backbone topography, the structural modification generates a potent and selective GABA(B) receptor agonist that inhibits Ca(v)2.2 channels and exhibits dose-dependent reversal of mechanical allodynia in a behavioral rat model of neuropathic pain. The findings herein support the hypothesis that analgesia can be achieved via activation of GABA(B)Rs expressed in dorsal root ganglion (DRG) sensory neurons.