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Author Notes:

Correspondence: S.F. Traynelis, Department of Pharmacology, Emory University School of Medicine, Atlanta, GA, USA; Tel.: +1 404 727 1375; Email: strayne@emory.edu and D.C. Liotta, Department of Chemistry, Emory University, Atlanta, GA, USA; Tel: +1 404 727 6602; Email: dliotta@emory.edu

Acknowledgements: The authors are grateful to Drs. S. Nakanishi, P. Seeburg, and S. F. Heinemann for cDNAs encoding the glutamate receptor subunits.

We thank Kimberly Vellano for excellent technical assistance.

Disclosures: Several of the authors (C.A.M., Y.A.T., L.J.W., S.J.M., R.D., S.F.T., D.C.L.) are inventors of Emory University owned patent-pending technology associated with these compounds, or have an equity position in companies actively seeking to license these compounds (D.C.L., S.F.T., R.D.).

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Research Funding:

This work was supported in part by the NINDS (NS036654, ST; NS036604, RD).

Keywords:

  • NMDA
  • GluN2B
  • NR2B-selective antagonists
  • Neuroprotection

Synthesis, structural activity-relationships, and biological evaluation of novel amide-based allosteric binding site antagonists in NR1A/NR2B N-methyl-D-aspartate receptors

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Journal Title:

Bioorganic and Medicinal Chemistry

Volume:

Volume 17, Number 17

Publisher:

, Pages 6463-6480

Type of Work:

Article | Post-print: After Peer Review

Abstract:

The synthesis and structure–activity relationship analysis of a novel class of amide-based biaryl NR2B-selective NMDA receptor antagonists are presented. Some of the studied compounds are potent, selective, non-competitive, and voltage-independent antagonists of NR2B-containing NMDA receptors. Like the founding member of this class of antagonists (ifenprodil), several interesting compounds of the series bind to the amino terminal domain of the NR2B subunit to inhibit function. Analogue potency is modu-lated by linker length, flexibility, and hydrogen bonding opportunities. However, unlike previously described classes of NR2B-selective NMDA antagonists that exhibit off-target activity at a variety of monoamine receptors, the compounds described herein show much diminished effects against the hERG channel and α1-adrenergic receptors. Selections of the compounds discussed have acceptable half-lives in vivo and are predicted to permeate the blood–brain barrier. These data together suggest that masking charged atoms on the linker region of NR2B-selective antagonists can decrease undesirable side effects while still maintaining on-target potency.

Copyright information:

© 2009 Published by Elsevier Ltd.

This is an Open Access work distributed under the terms of the Creative Commons Attribution-NonCommerical-NoDerivs 3.0 Unported License (http://creativecommons.org/licenses/by-nc-nd/3.0/).

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