Uncompetitive antagonism of AMPA receptors: Mechanistic insights from studies of polyamine toxin derivatives

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

SN - 0022-2623

VL - 49

SP - 5414

EP - 5423

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

IS - 18

ER -