The Effects of Conformational Constraints in the Polyamine Moiety of Philanthotoxins on AMPAR Inhibition. Issue 8 (8th July 2014)

• Record Type: Journal Article
• Authors: Franzyk, Henrik; Grzeskowiak, John W.; Tikhonov, Denis B.; Jaroszewski, Jerzy W.; Mellor, Ian R.
• Is Part Of: ChemMedChem. Volume 9:Issue 8(2014:Aug.)
• Page Start: 1725
• Page End: 1731
• Publication Date: 2014-07-08
• Subjects: Pharmaceutical chemistry -- Periodicals; 615.19005
• DOI: 10.1002/cmdc.201402109
• Languages: English
• ISSNs: 1860-7179

Abstract

<abstract abstract-type="main" xml:lang="en"> <title>Abstract</title> <p>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 <italic>Xenopus</italic> oocytes expressing the GluA1flop subunit. All analogues were found to be more potent than PhTX‐343, with <italic>trans</italic>‐cyclopropyl‐PhTX‐343 being the most potent (∼28‐fold) and <italic>cis</italic>‐cyclopropyl‐PhTX‐343 least potent (∼4‐fold). Both <italic>cis</italic>‐ and <italic>trans</italic>‐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 <italic>cis</italic> conformation due to enhanced intramolecular folding. Elongated PhTX‐444 analogues alleviate this to some extent, but optimal positioning of the amines is not permitted.</p> </abstract>