Abstract
| Original language | English |
|---|---|
| Pages (from-to) | 9933 - 9944 |
| Number of pages | 12 |
| Journal | Journal of Medicinal Chemistry |
| Volume | 57 |
| Issue number | 23 |
| DOIs | |
| Publication status | Published - 2014 |
Cite this
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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 journal › Article › Research › peer-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.
UR - http://pubs.acs.org/doi/pdf/10.1021/jm501126u
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 -