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

作者：Frolund Sidsel; Bella Angelo; Kristensen Anders S; Ziegler Hanne L; Witt Matthias; Olsen Christian A; Stromgaard Kristian; Franzyk Henrik; Jaroszewski Jerzy W^*

来源：Journal of Medicinal Chemistry, 2010, 53(20): 7441-7451.

DOI：10.1021/jm100886h

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 GluA l(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.

• 出版日期2010-10-28