TY - JOUR
T1 - Structure-activity relationship studies of argiotoxins
T2 - selective and potent inhibitors of ionotropic glutamate receptors
AU - Poulsen, Mette H
AU - Lucas, Simon
AU - Bach, Tinna B
AU - Barslund, Anne F
AU - Wenzler, Claudius
AU - Jensen, Christel B
AU - Kristensen, Anders S
AU - Strømgaard, Kristian
PY - 2013/2/14
Y1 - 2013/2/14
N2 - Argiotoxin-636 (ArgTX-636), a natural product from the spider Argiope lobata, is a potent but nonselective open-channel blocker of ionotropic glutamate (iGlu) receptors. Here, three series of analogues were designed to exploit selectivity among iGlu receptors, taking advantage of a recently developed solid-phase synthetic methodology for the synthesis of ArgTX-636 and analogues. Initially, the importance of secondary amino groups in the polyamine chain was studied by the synthesis of systematically modified ArgTX-636 analogues, which were evaluated for pharmacological activity at NMDA and AMPA receptors. This led to the identification of two compounds with preference for NMDA and AMPA receptors, respectively. These were further elaborated by systematically changing the aromatic headgroup and linker amino acid leading to compounds with increased potency and selectivity for NMDA and AMPA receptors, respectively. Thus, the first structure-activity relationship study of ArgTX-636 has been carried out and has provided lead compounds for probing the ion channel region of iGlu receptors.
AB - Argiotoxin-636 (ArgTX-636), a natural product from the spider Argiope lobata, is a potent but nonselective open-channel blocker of ionotropic glutamate (iGlu) receptors. Here, three series of analogues were designed to exploit selectivity among iGlu receptors, taking advantage of a recently developed solid-phase synthetic methodology for the synthesis of ArgTX-636 and analogues. Initially, the importance of secondary amino groups in the polyamine chain was studied by the synthesis of systematically modified ArgTX-636 analogues, which were evaluated for pharmacological activity at NMDA and AMPA receptors. This led to the identification of two compounds with preference for NMDA and AMPA receptors, respectively. These were further elaborated by systematically changing the aromatic headgroup and linker amino acid leading to compounds with increased potency and selectivity for NMDA and AMPA receptors, respectively. Thus, the first structure-activity relationship study of ArgTX-636 has been carried out and has provided lead compounds for probing the ion channel region of iGlu receptors.
KW - Chromatography, High Pressure Liquid
KW - Indoleacetic Acids
KW - Magnetic Resonance Spectroscopy
KW - Mass Spectrometry
KW - Polyamines
KW - Receptors, Ionotropic Glutamate
KW - Spectrometry, Mass, Electrospray Ionization
KW - Structure-Activity Relationship
U2 - 10.1021/jm301602d
DO - 10.1021/jm301602d
M3 - Journal article
C2 - 23320429
SN - 0022-2623
VL - 56
SP - 1171
EP - 1181
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
IS - 3
ER -