Solid-phase synthesis of polyamine toxin analogues: potent and selective antagonists of Ca2+-permeable AMPA receptors.
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.
Kromann
Hasse
H
Department of Medicinal Chemistry and NeuroScience PharmaBiotec Research Center, Royal Danish School of Pharmacy, Universitetsparken 2, DK-2100 Copenhagen, Denmark.
Krikstolaityte
Sonata
S
Andersen
Anne J
AJ
Andersen
Kim
K
Krogsgaard-Larsen
Povl
P
Jaroszewski
Jerzy W
JW
Egebjerg
Jan
J
Strømgaard
Kristian
K
D000818:Animals; D002118:Calcium / Q000378:metabolism*; D018691:Excitatory Amino Acid Antagonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D066298:In Vitro Techniques; D009865:Oocytes; D018408:Patch-Clamp Techniques; D011073:Polyamines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D018091:Receptors, AMPA / Q000037:antagonists & inhibitors* / Q000502:physiology; D018092:Kainic Acid Receptors / Q000037:antagonists & inhibitors / Q000502:physiology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014862:Wasp Venoms / Q000737:chemistry*; D014982:Xenopus laevis
D002118:Calcium; D018691:Excitatory Amino Acid Antagonists; D011073:Polyamines; D018091:Receptors, AMPA; D018092:Kainic Acid Receptors; D014862:Wasp Venoms; C104722:glutamate receptor ionotropic, AMPA 2