Assessment of Structurally Diverse Philanthotoxin Analogues for Inhibitory Activity on Ionotropic Glutamate Receptor Subtypes: Discovery of Nanomolar, Nonselective, and Use-Dependent Antagonists

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• 作者：Sidsel Frø ; lund ; Angelo Bella ; Anders S. Kristensen ; Hanne L. Ziegler ; Matthias Witt ; Christian A. Olsen ; Kristian Strø ; mgaard ; Henrik Franzyk ; Jerzy W. Jaroszewski
• 刊名：Journal of Medicinal Chemistry
• 出版年：2010
• 出版时间：October 28, 2010
• 年：2010
• 卷：53
• 期：20
• 页码：7441-7451
• 全文大小：985K
• 年卷期：v.53,no.20(October 28, 2010)
• ISSN：1520-4804

文摘

An array of analogues of the wasp toxin philanthotoxin-433, in which the asymmetric polyamine moiety was exchanged for spermine and the headgroup replaced with a variety of structurally diverse moieties, was prepared using parallel solid-phase synthesis approaches. In three analogues, the spermine moiety was extended with an amino acid tail, six compounds contained an N-acylated cyclohexylalanine, and four analogues were based on a novel diamino acid design with systematically changed spacer length between N-cyclohexylcarbonyl and N-phenylacetyl substituents. The analogues were studied using two-electrode voltage-clamp electrophysiology employing Xenopus laevis oocytes expressing GluA1_i AMPA or GluN1/2A NMDA receptors. Several of the analogues showed significantly increased inhibition of the GluN1/2A NMDA receptor. Thus, an analogue containing N-(1-naphtyl)acetyl group showed an IC₅₀ value of 47 nM. For the diamino acid-based analogues, the optimal spacer length between two N-acyl groups was determined, resulting in an analogue with an IC₅₀ value of 106 nM.