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Agonist discrimination between AMPA receptor subtypes

Coquelle, Thomas1; Christensen, Jeppe K.1; Banke, Tue G.1; Madsen, Ulf2; Schousboe, Arne1; Pickering, Darryl S.1,3

NEUROPHARMACOLOGY AND NEUROTOXICOLOGY

The lack of subtype-selective compounds for AMPA receptors (AMPA-R) led us to search for compounds with such selectivity. Homoibotenic acid analogues were investigated at recombinant GluR1o, GluR2o(R), GluR3o and GluR1o+ 3o receptors expressed in Sf9 insect cells and affinities determined in [3H]AMPA radioligand binding experiments. (S)-4-bromohomoibotenic acid (BrHIBO) exhibited a 126-fold selectivity for GluR1o compared to GluR3o. Xenopus laevis oocytes were used to express functional homomeric and heteromeric recombinant AMPA-R and to determine BrHIBO potency (EC50) at these channels. (R,S)-BrHIBO exhibited a 37-fold selectivity range amongst the AMPA-R. It is hoped that BrHIBO can be used as a lead structure for the development of other subtype-selective compounds.

1Neuroscience PharmaBiotec Research Center, Department of Pharmacology, The Royal Danish School of Pharmacy, 2 Universitetsparken, DK-2100 Copenhagen, Denmark

2Neuroscience PharmaBiotec Research Center, Department of Medicinal Chemistry, The Royal Danish School of Pharmacy, 2 Universitetsparken, DK-2100 Copenhagen, Denmark

3Corresponding Author: Darryl S. Pickering

Acknowledgements: This work was supported by grants from the Danish Medical Research Council (9700761; 9900019; 9900201) and the Lundbeck Foundation.

Received 17 May 2000; accepted 6 June 2000

© 2000 Lippincott Williams & Wilkins, Inc.