Design, synthesis, and pharmacological characterization of polyamine toxin derivatives: potent ligands for the pore-forming region of AMPA receptors

TY - JOUR

T1 - Design, synthesis, and pharmacological characterization of polyamine toxin derivatives

T2 - potent ligands for the pore-forming region of AMPA receptors

AU - Jensen, Lars S

AU - Bølcho, Ulrik

AU - Egebjerg, Jan

AU - Strømgaard, Kristian

PY - 2006/4

Y1 - 2006/4

N2 - Polyamine toxins, such as philanthotoxins, are low-molecular-weight compounds isolated from spiders and wasps, which modulate ligand-gated ion channels in the nervous system. Philanthotoxins bind to the pore-forming region of AMPA receptors, a subtype of glutamate receptors which are important for memory formation and are involved in neurodegenerative diseases. Previous studies have demonstrated that modification of the polyamine moiety of philanthotoxins can lead to very potent and highly selective ligands for the AMPA receptor, as exemplified with philanthotoxin-56. Much less attention has been paid to the importance of the aromatic head group of philanthotoxins, but herein we demonstrate that modification of this moiety leads to a significant improvement in potency relative to philanthotoxin-56 at cloned AMPA receptors. Interestingly, the incorporation of an adamantane moiety is particularly favorable, and the most potent compound has a Ki value of 2 nM, making it the most potent uncompetitive antagonist of AMPA receptors described to date. Such compounds are potentially useful as neuroprotective agents.

AB - Polyamine toxins, such as philanthotoxins, are low-molecular-weight compounds isolated from spiders and wasps, which modulate ligand-gated ion channels in the nervous system. Philanthotoxins bind to the pore-forming region of AMPA receptors, a subtype of glutamate receptors which are important for memory formation and are involved in neurodegenerative diseases. Previous studies have demonstrated that modification of the polyamine moiety of philanthotoxins can lead to very potent and highly selective ligands for the AMPA receptor, as exemplified with philanthotoxin-56. Much less attention has been paid to the importance of the aromatic head group of philanthotoxins, but herein we demonstrate that modification of this moiety leads to a significant improvement in potency relative to philanthotoxin-56 at cloned AMPA receptors. Interestingly, the incorporation of an adamantane moiety is particularly favorable, and the most potent compound has a Ki value of 2 nM, making it the most potent uncompetitive antagonist of AMPA receptors described to date. Such compounds are potentially useful as neuroprotective agents.

KW - Animals

KW - Chromatography, High Pressure Liquid

KW - Drug Design

KW - Ligands

KW - Magnetic Resonance Spectroscopy

KW - Polyamines

KW - Receptors, AMPA

KW - Xenopus

U2 - 10.1002/cmdc.200500093

DO - 10.1002/cmdc.200500093

M3 - Journal article

C2 - 16892377

SN - 1860-7179

VL - 1

SP - 419

EP - 428

JO - Farmaco, Edizione Pratica

JF - Farmaco, Edizione Pratica

IS - 4

ER -