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Author Notes:

To whom correspondence should be addressed. For S.F.T.: Phone, +1-404-727-0357; Fax, +1-404-727-0365; strayne@emory.edu. For J.P.S.: Phone, 404-727-2415; Fax, +1-404-727-6586; jsnyder@emory.edu

Department of Chemistry, Emory University.

Department of Pharmacology, Emory University School of Medicine.

Department of Neurobiology, Duke University.

FOB Synthesis, Inc., Emtech Bio (Emory University and Georgia Tech).

Several of the authors (Y.A.T., J.P.S., D.L., R.D., S.F.T., J.O.M.) 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 (JPS, DL, RD, SFT)

We thank Drs. Elias Aizenman, Stephen Heinemann, Shigetada Nakanishi, Pierre Paoletti, and Peter Seeburg for sharing cDNA for glutamate receptors and mutants, and Dr. Mark Washburn for assistance in several of the biological assays.

We are also grateful to OpenEye Scientific Software (Santa Fe, NM) for the generous provision of a no-cost license to use software for the conformational analyses described.

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Research Funding:

This work was supported by NIH-NINDS (NS036654, NS039419 S.T.), NARSAD (S.T.), NIH-NINDS (NS036604, R.D.), NIH-NINDS NS056217 (J.O.M.), the Michael J. Fox Foundation (S.T.), and Parents Against Childhood Epilepsy, Inc. Research Grant Program (R.D.).

Enantiomeric Propanolamines as selective N-Methyl-d-aspartate 2B Receptor Antagonists†

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Journal Title:

Journal of Medicinal Chemistry

Volume:

Volume 51, Number 18

Publisher:

, Pages 5506-5521

Type of Work:

Article | Post-print: After Peer Review

Abstract:

Enantiomeric propanolamines have been identified as a new class of NR2B-selective NMDA receptor antagonists. The most effective agents are biaryl structures, synthesized in six steps with overall yields ranging from 11–64%. The compounds are potent and selective inhibitors of NR2B-containing recombinant NMDA receptors with IC50 values between 30–100 nM. Potency is strongly controlled by substitution on both rings and the centrally located amine nitrogen. SAR analysis suggests that well-balanced polarity and chain-length factors provide the greatest inhibitory potency. Structural comparisons based on 3D shape analysis and electrostatic complementarity support this conclusion. The antagonists are neuroprotective in both in vitro and in vivo models of ischemic cell death. In addition, some compounds exhibit anticonvulsant properties. Unlike earlier generation NMDA receptor antagonists and some NR2B-selective antagonists, the present series of propanolamines does not cause increased locomotion in rodents. Thus, the NR2B-selective antagonists exhibit a range of therapeutically interesting properties.

Copyright information:

© 2008 American Chemical Society

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