Uncompetitive antagonism of AMPA receptors: Mechanistic insights from studies of polyamine toxin derivatives
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Uncompetitive antagonism of AMPA receptors : Mechanistic insights from studies of polyamine toxin derivatives. / Andersen, Trine F; Tikhonov, Denis B; Bølcho, Ulrik; Bolshakov, Konstantin; Nelson, Jared K; Pluteanu, Florentina; Mellor, Ian R; Egebjerg, Jan; Strømgaard, Kristian.
In: Journal of Medicinal Chemistry, Vol. 49, No. 18, 07.09.2006, p. 5414-5423.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - Uncompetitive antagonism of AMPA receptors
T2 - Mechanistic insights from studies of polyamine toxin derivatives
AU - Andersen, Trine F
AU - Tikhonov, Denis B
AU - Bølcho, Ulrik
AU - Bolshakov, Konstantin
AU - Nelson, Jared K
AU - Pluteanu, Florentina
AU - Mellor, Ian R
AU - Egebjerg, Jan
AU - Strømgaard, Kristian
PY - 2006/9/7
Y1 - 2006/9/7
N2 - Philanthotoxins are uncompetitive antagonists of Ca2+-permeable AMPA receptors presumed to bind to the pore-forming region, but a detailed molecular mechanism for this interaction is missing. Here a small library of novel philanthotoxins was designed and synthesized using a solid-phase strategy. The biological activities were investigated at cloned and "native" AMPA receptors using electrophysiological techniques. A distinct relationship between length of the polyamine moiety and the location of a secondary amino group was observed. Fitting the data to the Woodhull equation allowed the first experimental demonstration of the relative location and orientation of the philanthotoxin molecule in the receptor. These results were corroborated by in silico studies using a homology model of the AMPA receptor ion channel. Together these studies provide strong evidence for a molecular mechanism by which polyamine toxins antagonize the AMPA receptor ion channel and provide the basis for rational development of uncompetitive antagonists of AMPA receptors.
AB - Philanthotoxins are uncompetitive antagonists of Ca2+-permeable AMPA receptors presumed to bind to the pore-forming region, but a detailed molecular mechanism for this interaction is missing. Here a small library of novel philanthotoxins was designed and synthesized using a solid-phase strategy. The biological activities were investigated at cloned and "native" AMPA receptors using electrophysiological techniques. A distinct relationship between length of the polyamine moiety and the location of a secondary amino group was observed. Fitting the data to the Woodhull equation allowed the first experimental demonstration of the relative location and orientation of the philanthotoxin molecule in the receptor. These results were corroborated by in silico studies using a homology model of the AMPA receptor ion channel. Together these studies provide strong evidence for a molecular mechanism by which polyamine toxins antagonize the AMPA receptor ion channel and provide the basis for rational development of uncompetitive antagonists of AMPA receptors.
KW - Animals
KW - Bacterial Proteins
KW - Binding Sites
KW - Calcium
KW - Models, Molecular
KW - Molecular Structure
KW - Oocytes
KW - Patch-Clamp Techniques
KW - Polyamines
KW - Potassium Channels
KW - Rats
KW - Receptors, AMPA
KW - Stereoisomerism
KW - Structure-Activity Relationship
KW - Toxins, Biological
KW - Tyrosine
KW - Wasp Venoms
KW - Xenopus laevis
U2 - 10.1021/jm060606j
DO - 10.1021/jm060606j
M3 - Journal article
C2 - 16942015
VL - 49
SP - 5414
EP - 5423
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
SN - 0022-2623
IS - 18
ER -
ID: 45823493