Solid-phase synthesis of polyamine toxin analogues: potent and selective antagonists of Ca2+-permeable AMPA receptors

Research output: Contribution to journalJournal articleResearchpeer-review

Standard

Solid-phase synthesis of polyamine toxin analogues : potent and selective antagonists of Ca2+-permeable AMPA receptors. / Kromann, Hasse; Krikstolaityte, Sonata; Andersen, Anne J; Andersen, Kim; Krogsgaard-Larsen, Povl; Jaroszewski, Jerzy W; Egebjerg, Jan; Strømgaard, Kristian.

In: Journal of Medicinal Chemistry, Vol. 45, No. 26, 19.12.2002, p. 5745-5754.

Research output: Contribution to journalJournal articleResearchpeer-review

Harvard

Kromann, H, Krikstolaityte, S, Andersen, AJ, Andersen, K, Krogsgaard-Larsen, P, Jaroszewski, JW, Egebjerg, J & Strømgaard, K 2002, 'Solid-phase synthesis of polyamine toxin analogues: potent and selective antagonists of Ca2+-permeable AMPA receptors', Journal of Medicinal Chemistry, vol. 45, no. 26, pp. 5745-5754.

APA

Kromann, H., Krikstolaityte, S., Andersen, A. J., Andersen, K., Krogsgaard-Larsen, P., Jaroszewski, J. W., ... Strømgaard, K. (2002). Solid-phase synthesis of polyamine toxin analogues: potent and selective antagonists of Ca2+-permeable AMPA receptors. Journal of Medicinal Chemistry, 45(26), 5745-5754.

Vancouver

Kromann H, Krikstolaityte S, Andersen AJ, Andersen K, Krogsgaard-Larsen P, Jaroszewski JW et al. Solid-phase synthesis of polyamine toxin analogues: potent and selective antagonists of Ca2+-permeable AMPA receptors. Journal of Medicinal Chemistry. 2002 Dec 19;45(26):5745-5754.

Author

Kromann, Hasse ; Krikstolaityte, Sonata ; Andersen, Anne J ; Andersen, Kim ; Krogsgaard-Larsen, Povl ; Jaroszewski, Jerzy W ; Egebjerg, Jan ; Strømgaard, Kristian. / Solid-phase synthesis of polyamine toxin analogues : potent and selective antagonists of Ca2+-permeable AMPA receptors. In: Journal of Medicinal Chemistry. 2002 ; Vol. 45, No. 26. pp. 5745-5754.

Bibtex

@article{abfed1c6668243d68e93edf53e9150b8,
title = "Solid-phase synthesis of polyamine toxin analogues: potent and selective antagonists of Ca2+-permeable AMPA receptors",
abstract = "The wasp toxin philanthotoxin-433 (PhTX-433) is a nonselective and noncompetitive antagonist of ionotropic receptors, such as ionotropic glutamate receptors and nicotinic acetylcholine receptors. Polyamine toxins are extensively used for the characterization of subtypes of ionotropic glutamate receptors, in particular Ca(2+)-permeable AMPA and kainate receptors. We have previously shown that an analogue of PhTX-433 with one of the amino groups replaced by a methylene group, philanthotoxin-83 (PhTX-83) is a selective and potent antagonist of AMPA receptors. We now describe the solid-phase synthesis of analogues of PhTX-83 and the electrophysiological characterization of these analogues on cloned AMPA and kainate receptors. The polyamine portion of PhTX-83 was modified systematically by changing the position of the secondary amino group along the polyamine chain. In another series of analogues, the acyl moiety of PhTX-83 was replaced by acids of different size and lipophilicity. Using electrophysiological techniques, PhTX-56 was shown to be a highly potent (K(i) = 3.3 +/- 0.78 nM) and voltage-dependent antagonist of homomeric GluR1 receptors and was more than 1000-fold less potent when tested on heteromeric GluR1+GluR2, as well as homomeric GluR5(Q) receptors, thus being selective for Ca(2+)-permeable AMPA receptors. Variation of the acyl group of PhTX-83 had only minor effect on antagonist potency at homomeric GluR1 receptors but led to a significant decrease in the voltage-dependence. In conclusion, PhTX-56 is a novel, very potent, and selective antagonist of Ca(2+)-permeable AMPA receptors and is a promising tool for structure/function studies of the ion channel of the AMPA receptor.",
keywords = "Animals, Calcium, Excitatory Amino Acid Antagonists, Oocytes, Patch-Clamp Techniques, Polyamines, Receptors, AMPA, Receptors, Kainic Acid, Stereoisomerism, Structure-Activity Relationship, Wasp Venoms, Xenopus laevis",
author = "Hasse Kromann and Sonata Krikstolaityte and Andersen, {Anne J} and Kim Andersen and Povl Krogsgaard-Larsen and Jaroszewski, {Jerzy W} and Jan Egebjerg and Kristian Str{\o}mgaard",
year = "2002",
month = "12",
day = "19",
language = "English",
volume = "45",
pages = "5745--5754",
journal = "Journal of Medicinal Chemistry",
issn = "0022-2623",
publisher = "American Chemical Society",
number = "26",

}

RIS

TY - JOUR

T1 - Solid-phase synthesis of polyamine toxin analogues

T2 - potent and selective antagonists of Ca2+-permeable AMPA receptors

AU - Kromann, Hasse

AU - Krikstolaityte, Sonata

AU - Andersen, Anne J

AU - Andersen, Kim

AU - Krogsgaard-Larsen, Povl

AU - Jaroszewski, Jerzy W

AU - Egebjerg, Jan

AU - Strømgaard, Kristian

PY - 2002/12/19

Y1 - 2002/12/19

N2 - The wasp toxin philanthotoxin-433 (PhTX-433) is a nonselective and noncompetitive antagonist of ionotropic receptors, such as ionotropic glutamate receptors and nicotinic acetylcholine receptors. Polyamine toxins are extensively used for the characterization of subtypes of ionotropic glutamate receptors, in particular Ca(2+)-permeable AMPA and kainate receptors. We have previously shown that an analogue of PhTX-433 with one of the amino groups replaced by a methylene group, philanthotoxin-83 (PhTX-83) is a selective and potent antagonist of AMPA receptors. We now describe the solid-phase synthesis of analogues of PhTX-83 and the electrophysiological characterization of these analogues on cloned AMPA and kainate receptors. The polyamine portion of PhTX-83 was modified systematically by changing the position of the secondary amino group along the polyamine chain. In another series of analogues, the acyl moiety of PhTX-83 was replaced by acids of different size and lipophilicity. Using electrophysiological techniques, PhTX-56 was shown to be a highly potent (K(i) = 3.3 +/- 0.78 nM) and voltage-dependent antagonist of homomeric GluR1 receptors and was more than 1000-fold less potent when tested on heteromeric GluR1+GluR2, as well as homomeric GluR5(Q) receptors, thus being selective for Ca(2+)-permeable AMPA receptors. Variation of the acyl group of PhTX-83 had only minor effect on antagonist potency at homomeric GluR1 receptors but led to a significant decrease in the voltage-dependence. In conclusion, PhTX-56 is a novel, very potent, and selective antagonist of Ca(2+)-permeable AMPA receptors and is a promising tool for structure/function studies of the ion channel of the AMPA receptor.

AB - The wasp toxin philanthotoxin-433 (PhTX-433) is a nonselective and noncompetitive antagonist of ionotropic receptors, such as ionotropic glutamate receptors and nicotinic acetylcholine receptors. Polyamine toxins are extensively used for the characterization of subtypes of ionotropic glutamate receptors, in particular Ca(2+)-permeable AMPA and kainate receptors. We have previously shown that an analogue of PhTX-433 with one of the amino groups replaced by a methylene group, philanthotoxin-83 (PhTX-83) is a selective and potent antagonist of AMPA receptors. We now describe the solid-phase synthesis of analogues of PhTX-83 and the electrophysiological characterization of these analogues on cloned AMPA and kainate receptors. The polyamine portion of PhTX-83 was modified systematically by changing the position of the secondary amino group along the polyamine chain. In another series of analogues, the acyl moiety of PhTX-83 was replaced by acids of different size and lipophilicity. Using electrophysiological techniques, PhTX-56 was shown to be a highly potent (K(i) = 3.3 +/- 0.78 nM) and voltage-dependent antagonist of homomeric GluR1 receptors and was more than 1000-fold less potent when tested on heteromeric GluR1+GluR2, as well as homomeric GluR5(Q) receptors, thus being selective for Ca(2+)-permeable AMPA receptors. Variation of the acyl group of PhTX-83 had only minor effect on antagonist potency at homomeric GluR1 receptors but led to a significant decrease in the voltage-dependence. In conclusion, PhTX-56 is a novel, very potent, and selective antagonist of Ca(2+)-permeable AMPA receptors and is a promising tool for structure/function studies of the ion channel of the AMPA receptor.

KW - Animals

KW - Calcium

KW - Excitatory Amino Acid Antagonists

KW - Oocytes

KW - Patch-Clamp Techniques

KW - Polyamines

KW - Receptors, AMPA

KW - Receptors, Kainic Acid

KW - Stereoisomerism

KW - Structure-Activity Relationship

KW - Wasp Venoms

KW - Xenopus laevis

M3 - Journal article

C2 - 12477358

VL - 45

SP - 5745

EP - 5754

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

SN - 0022-2623

IS - 26

ER -

ID: 45824294