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Dicarba analogues of α-conotoxin RgIA. Structure, stability, and activity at potential pain targets

Journal Article


Abstract


  • α-Conotoxin RgIA is both an antagonist of the α9α10 nicotinic acetylcholine receptor (nAChR) subtype and an inhibitor of high-voltage-activated N-type calcium channel currents. RgIA has therapeutic potential for the treatment of pain, but reduction of the disulfide bond framework under physiological conditions represents a potential liability for clinical applications. We synthesized four RgIA analogues that replaced native disulfide pairs with nonreducible dicarba bridges. Solution structures were determined by NMR, activity assessed against biological targets, and stability evaluated in human serum. [3,12]-Dicarba analogues retained inhibition of ACh-evoked currents at α9α10 nAChRs but not N-type calcium channel currents, whereas [2,8]-dicarba analogues displayed the opposite pattern of selectivity. The [2,8]-dicarba RgIA analogues were effective in HEK293 cells stably expressing human Cav2.2 channels and transfected with human GABAB receptors. The analogues also exhibited improved serum stability over the native peptide. These selectively acting dicarba analogues may represent mechanistic probes to explore analgesia-related biological receptors.

UOW Authors


  •   Chhabra, Sandeep (external author)
  •   Belgi, Alessia (external author)
  •   Bartels, Peter (external author)
  •   van Lierop, Bianca J. (external author)
  •   Robinson, Samuel D. (external author)
  •   Kompella, Shiva N. (external author)
  •   Hung, Andrew (external author)
  •   Callaghan, Brid P. (external author)
  •   Adams, David
  •   Robinson, Andrea J. (external author)
  •   Norton, Raymond (external author)

Publication Date


  • 2014

Citation


  • Chhabra, S., Belgi, A., Bartels, P., Van Lierop, B. J., Robinson, S. D., Kompella, S. N., Hung, A., Callaghan, B. P., Adams, D. J., Robinson, A. J. & Norton, R. (2014). Dicarba analogues of α-conotoxin RgIA. Structure, stability, and activity at potential pain targets. Journal of Medicinal Chemistry, 57 (23), 9933-9944.

Scopus Eid


  • 2-s2.0-84918492290

Ro Metadata Url


  • http://ro.uow.edu.au/ihmri/591

Number Of Pages


  • 11

Start Page


  • 9933

End Page


  • 9944

Volume


  • 57

Issue


  • 23

Abstract


  • α-Conotoxin RgIA is both an antagonist of the α9α10 nicotinic acetylcholine receptor (nAChR) subtype and an inhibitor of high-voltage-activated N-type calcium channel currents. RgIA has therapeutic potential for the treatment of pain, but reduction of the disulfide bond framework under physiological conditions represents a potential liability for clinical applications. We synthesized four RgIA analogues that replaced native disulfide pairs with nonreducible dicarba bridges. Solution structures were determined by NMR, activity assessed against biological targets, and stability evaluated in human serum. [3,12]-Dicarba analogues retained inhibition of ACh-evoked currents at α9α10 nAChRs but not N-type calcium channel currents, whereas [2,8]-dicarba analogues displayed the opposite pattern of selectivity. The [2,8]-dicarba RgIA analogues were effective in HEK293 cells stably expressing human Cav2.2 channels and transfected with human GABAB receptors. The analogues also exhibited improved serum stability over the native peptide. These selectively acting dicarba analogues may represent mechanistic probes to explore analgesia-related biological receptors.

UOW Authors


  •   Chhabra, Sandeep (external author)
  •   Belgi, Alessia (external author)
  •   Bartels, Peter (external author)
  •   van Lierop, Bianca J. (external author)
  •   Robinson, Samuel D. (external author)
  •   Kompella, Shiva N. (external author)
  •   Hung, Andrew (external author)
  •   Callaghan, Brid P. (external author)
  •   Adams, David
  •   Robinson, Andrea J. (external author)
  •   Norton, Raymond (external author)

Publication Date


  • 2014

Citation


  • Chhabra, S., Belgi, A., Bartels, P., Van Lierop, B. J., Robinson, S. D., Kompella, S. N., Hung, A., Callaghan, B. P., Adams, D. J., Robinson, A. J. & Norton, R. (2014). Dicarba analogues of α-conotoxin RgIA. Structure, stability, and activity at potential pain targets. Journal of Medicinal Chemistry, 57 (23), 9933-9944.

Scopus Eid


  • 2-s2.0-84918492290

Ro Metadata Url


  • http://ro.uow.edu.au/ihmri/591

Number Of Pages


  • 11

Start Page


  • 9933

End Page


  • 9944

Volume


  • 57

Issue


  • 23