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Alkyne-Bridged ¿-Conotoxin Vc1.1 Potently Reverses Mechanical Allodynia in Neuropathic Pain Models

Journal Article


Abstract


  • Several Conus-derived venom peptides are promising lead compounds for the management of neuropathic pain, with α-conotoxins being of particular interest. Modification of the interlocked disulfide framework of α-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 GABAB receptor agonist that inhibits Cav2.2 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 GABABRs expressed in dorsal root ganglion (DRG) sensory neurons.

Publication Date


  • 2021

Citation


  • Belgi, A., Burnley, J. V., MacRaild, C. A., Chhabra, S., Elnahriry, K. A., Robinson, S. D., . . . Robinson, A. J. (2021). Alkyne-Bridged ¿-Conotoxin Vc1.1 Potently Reverses Mechanical Allodynia in Neuropathic Pain Models. Journal of Medicinal Chemistry, 64(6), 3222-3233. doi:10.1021/acs.jmedchem.0c02151

Scopus Eid


  • 2-s2.0-85103607454

Start Page


  • 3222

End Page


  • 3233

Volume


  • 64

Issue


  • 6

Abstract


  • Several Conus-derived venom peptides are promising lead compounds for the management of neuropathic pain, with α-conotoxins being of particular interest. Modification of the interlocked disulfide framework of α-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 GABAB receptor agonist that inhibits Cav2.2 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 GABABRs expressed in dorsal root ganglion (DRG) sensory neurons.

Publication Date


  • 2021

Citation


  • Belgi, A., Burnley, J. V., MacRaild, C. A., Chhabra, S., Elnahriry, K. A., Robinson, S. D., . . . Robinson, A. J. (2021). Alkyne-Bridged ¿-Conotoxin Vc1.1 Potently Reverses Mechanical Allodynia in Neuropathic Pain Models. Journal of Medicinal Chemistry, 64(6), 3222-3233. doi:10.1021/acs.jmedchem.0c02151

Scopus Eid


  • 2-s2.0-85103607454

Start Page


  • 3222

End Page


  • 3233

Volume


  • 64

Issue


  • 6