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The Effects of Conformational Constraints in the Polyamine Moiety of Philanthotoxins on AMPAR Inhibition

Franzyk, Henrik; Grzeskowiak, John W.; Tikhonov, Denis B.; Jaroszewski, Jerzy W.; Mellor, Ian R.

Authors

Henrik Franzyk

John W. Grzeskowiak

Denis B. Tikhonov

Jerzy W. Jaroszewski

Ian R. Mellor



Abstract

Philanthotoxin‐433 (PhTX‐433) is a known potent inhibitor of ionotropic glutamate receptors, and analogues have been synthesised to identify more potent and selective antagonists. Herein we report the synthesis of four PhTXs with a cyclopropane moiety introduced into their polyamine chain, and their inhibition of an α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid (AMPA) receptor subtype by using two‐electrode voltage‐clamp assays on Xenopus oocytes expressing the GluA1flop subunit. All analogues were found to be more potent than PhTX‐343, with trans‐cyclopropyl‐PhTX‐343 being the most potent (∼28‐fold) and cis‐cyclopropyl‐PhTX‐343 least potent (∼4‐fold). Both cis‐ and trans‐cyclopropyl‐PhTX‐444 had intermediate potency (both ∼12‐fold). Molecular modelling indicates that a cyclopropane moiety confers a favourable steric constraint to the polyamine part, but this is compromised by a cis conformation due to enhanced intramolecular folding. Elongated PhTX‐444 analogues alleviate this to some extent, but optimal positioning of the amines is not permitted.

Journal Article Type Article
Publication Date Aug 1, 2014
Journal ChemMedChem
Print ISSN 1860-7179
Electronic ISSN 1860-7179
Publisher Wiley
Peer Reviewed Peer Reviewed
Volume 9
Issue 8
Pages 1725-1731
APA6 Citation Franzyk, H., Grzeskowiak, J. W., Tikhonov, D. B., Jaroszewski, J. W., & Mellor, I. R. (2014). The Effects of Conformational Constraints in the Polyamine Moiety of Philanthotoxins on AMPAR Inhibition. ChemMedChem, 9(8), 1725-1731. https://doi.org/10.1002/cmdc.201402109
DOI https://doi.org/10.1002/cmdc.201402109
Keywords glutamate receptors; ion channels; natural products; polyamine toxins; solid-phase synthesis
Publisher URL https://onlinelibrary.wiley.com/doi/abs/10.1002/cmdc.201402109
Copyright Statement Copyright information regarding this work can be found at the following address: http://eprints.nottingh.../end_user_agreement.pdf

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Copyright Statement
Copyright information regarding this work can be found at the following address: http://eprints.nottingham.ac.uk/end_user_agreement.pdf





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