ω-Conotoxin GVIA mimetics based on an anthranilamide core: Effect of variation in ammonium side chain lengths and incorporation of fluorine

Asa Andersson; Jonathan B. Baell; Peter J. Duggan; Janease E. Graham; Richard J. Lewis; Natalie G. Lumsden; C. Elisabet Tranberg; Kellie L. Tuck; Aijun Yang

doi:10.1016/j.bmc.2009.07.063

ω-Conotoxin GVIA mimetics based on an anthranilamide core: Effect of variation in ammonium side chain lengths and incorporation of fluorine

Asa Andersson, Jonathan B. Baell, Peter J. Duggan, Janease E. Graham, Richard J. Lewis, Natalie G. Lumsden, C. Elisabet Tranberg, Kellie L. Tuck, Aijun Yang

Research output: Contribution to journal › Article › peer-review

15 Citations (Scopus)

Abstract

A number of ω-conotoxin GVIA mimetics based on an anthranilamide core were prepared and tested for their affinity for rat brain Ca_v2.2 channels. Features such as the presence of hydroxyl and fluoro substituents on the tyrosine side chain mimic, the length of the chains on the lysine/arginine side chain mimics and the use of diguanidino and diamino substituents rather than mono-guanidine/mono-amine substitution were examined. The diguanidinylated compounds proved to be the most active and deletion of the hydroxyl substituent had a limited influence on activity. The SAR associated with variation in the lysine/arginine side chain mimics was not strong. The introduction of a fluoro substituent into the tyrosine mimic produced the most active compound prepared in this study (2g), with an EC₅₀ at rat brain Ca_v2.2 channels of 6 μM. Crown

Original language	English
Pages (from-to)	6659-6670
Number of pages	12
Journal	Bioorganic and Medicinal Chemistry
Volume	17
Issue number	18
DOIs	https://doi.org/10.1016/j.bmc.2009.07.063
Publication status	Published - 15 Sept 2009
Externally published	Yes

Keywords

Ca2.2
Channel blockers
Conotoxin
N-type calcium channels
Pain

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Andersson, A., Baell, J. B., Duggan, P. J., Graham, J. E., Lewis, R. J., Lumsden, N. G., Tranberg, C. E., Tuck, K. L., & Yang, A. (2009). ω-Conotoxin GVIA mimetics based on an anthranilamide core: Effect of variation in ammonium side chain lengths and incorporation of fluorine. Bioorganic and Medicinal Chemistry, 17(18), 6659-6670. https://doi.org/10.1016/j.bmc.2009.07.063

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abstract = "A number of ω-conotoxin GVIA mimetics based on an anthranilamide core were prepared and tested for their affinity for rat brain Cav2.2 channels. Features such as the presence of hydroxyl and fluoro substituents on the tyrosine side chain mimic, the length of the chains on the lysine/arginine side chain mimics and the use of diguanidino and diamino substituents rather than mono-guanidine/mono-amine substitution were examined. The diguanidinylated compounds proved to be the most active and deletion of the hydroxyl substituent had a limited influence on activity. The SAR associated with variation in the lysine/arginine side chain mimics was not strong. The introduction of a fluoro substituent into the tyrosine mimic produced the most active compound prepared in this study (2g), with an EC50 at rat brain Cav2.2 channels of 6 μM. Crown",

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author = "Asa Andersson and Baell, {Jonathan B.} and Duggan, {Peter J.} and Graham, {Janease E.} and Lewis, {Richard J.} and Lumsden, {Natalie G.} and Tranberg, {C. Elisabet} and Tuck, {Kellie L.} and Aijun Yang",

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doi = "10.1016/j.bmc.2009.07.063",

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AU - Andersson, Asa

AU - Baell, Jonathan B.

AU - Duggan, Peter J.

AU - Graham, Janease E.

AU - Lewis, Richard J.

AU - Lumsden, Natalie G.

AU - Tranberg, C. Elisabet

AU - Tuck, Kellie L.

AU - Yang, Aijun

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KW - Ca2.2

KW - Channel blockers

KW - Conotoxin

KW - N-type calcium channels

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ER -

ω-Conotoxin GVIA mimetics based on an anthranilamide core: Effect of variation in ammonium side chain lengths and incorporation of fluorine

Abstract

Keywords

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