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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.
Original language | English |
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Pages (from-to) | 3222–3233 |
Number of pages | 12 |
Journal | Journal of Medicinal Chemistry |
Volume | 64 |
Issue number | 6 |
DOIs | |
Publication status | Published - 16 Mar 2021 |
Projects
- 1 Finished