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

Sandeep Chhabra, Alessia Belgi, Peter Bartels, Bianca Jane Van Lierop, Samuel Robinson, Shiva Nag Kompella, Andrew Hung, Brid Callaghan, David John Adams, Andrea Jane Robinson, Raymond Stanley Norton

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Abstract

a-Conotoxin RgIA is both an antagonist of the a9a10 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 a9a10 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.
Original languageEnglish
Pages (from-to)9933 - 9944
Number of pages12
JournalJournal of Medicinal Chemistry
Volume57
Issue number23
DOIs
Publication statusPublished - 2014

Cite this

Chhabra, Sandeep ; Belgi, Alessia ; Bartels, Peter ; Van Lierop, Bianca Jane ; Robinson, Samuel ; Kompella, Shiva Nag ; Hung, Andrew ; Callaghan, Brid ; Adams, David John ; Robinson, Andrea Jane ; Norton, Raymond Stanley. / Dicarba analogues of a-conotoxin RgIA. Structure, stability, and activity at potential pain targets. In: Journal of Medicinal Chemistry. 2014 ; Vol. 57, No. 23. pp. 9933 - 9944.
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abstract = "a-Conotoxin RgIA is both an antagonist of the a9a10 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 a9a10 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.",
author = "Sandeep Chhabra and Alessia Belgi and Peter Bartels and {Van Lierop}, {Bianca Jane} and Samuel Robinson and Kompella, {Shiva Nag} and Andrew Hung and Brid Callaghan and Adams, {David John} and Robinson, {Andrea Jane} and Norton, {Raymond Stanley}",
year = "2014",
doi = "10.1021/jm501126u",
language = "English",
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Chhabra, S, Belgi, A, Bartels, P, Van Lierop, BJ, Robinson, S, Kompella, SN, Hung, A, Callaghan, B, Adams, DJ, Robinson, AJ & Norton, RS 2014, 'Dicarba analogues of a-conotoxin RgIA. Structure, stability, and activity at potential pain targets', Journal of Medicinal Chemistry, vol. 57, no. 23, pp. 9933 - 9944. https://doi.org/10.1021/jm501126u

Dicarba analogues of a-conotoxin RgIA. Structure, stability, and activity at potential pain targets. / Chhabra, Sandeep; Belgi, Alessia; Bartels, Peter; Van Lierop, Bianca Jane; Robinson, Samuel; Kompella, Shiva Nag; Hung, Andrew; Callaghan, Brid; Adams, David John; Robinson, Andrea Jane; Norton, Raymond Stanley.

In: Journal of Medicinal Chemistry, Vol. 57, No. 23, 2014, p. 9933 - 9944.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Dicarba analogues of a-conotoxin RgIA. Structure, stability, and activity at potential pain targets

AU - Chhabra, Sandeep

AU - Belgi, Alessia

AU - Bartels, Peter

AU - Van Lierop, Bianca Jane

AU - Robinson, Samuel

AU - Kompella, Shiva Nag

AU - Hung, Andrew

AU - Callaghan, Brid

AU - Adams, David John

AU - Robinson, Andrea Jane

AU - Norton, Raymond Stanley

PY - 2014

Y1 - 2014

N2 - a-Conotoxin RgIA is both an antagonist of the a9a10 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 a9a10 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.

AB - a-Conotoxin RgIA is both an antagonist of the a9a10 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 a9a10 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.

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U2 - 10.1021/jm501126u

DO - 10.1021/jm501126u

M3 - Article

VL - 57

SP - 9933

EP - 9944

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

SN - 0022-2623

IS - 23

ER -