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 -