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

VL - 56

SP - 1171

EP - 1181

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

SN - 0022-2623

IS - 3

ER -