Synthesis and characterization of a series of diarylguanidines that are noncompetitive N-methyl-D-aspartate receptor antagonists with neuroprotective properties

J. F W Keana, R. N. McBurney, M. W. Scherz, J. B. Fischer, P. N. Hamilton, Stephen Smith, A. C. Server, S. Finkbeiner, C. F. Stevens, Craig Jahr, E. Weber

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Abstract

Four diarylguanidine derivatives were synthesized. These compounds were found to displace, at submicromolar concentrations, 3H-labeled 1-[1-(2-thienyl)cyclohexyl]piperidine and (+)-[3H]MK-801 from phencyclidine receptors in brain membrane preparations. In electrophysiological experiments the diarylguanidines blocked N-methyl-D-aspartate (NMDA)-activated ion channels. These diarylguanidines also protected rat hippocampal neurons in vitro from glutamate-induced cell death. Our results show that some diarylguanidines are noncompetitive antagonists of NMDA receptor-mediated responses and have the neuroprotective property that is commonly associated with blockers of the NMDA receptor-gated cation channel. Diarylguanidines are structurally unrelated to known blockers of NMDA channels and, therefore, represent a new compound series for the development of neuroprotective agents with therapeutic value in patients suffering from stroke, from brain or spinal cord trauma, from hypoglycemia, and possibly from brain ischemia due to heart attack.

Original languageEnglish (US)
Pages (from-to)5631-5635
Number of pages5
JournalProceedings of the National Academy of Sciences of the United States of America
Volume86
Issue number14
StatePublished - 1989

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tenocyclidine
N-Methylaspartate
N-Methyl-D-Aspartate Receptors
Phencyclidine Receptors
Dizocilpine Maleate
Brain
Neuroprotective Agents
Brain Ischemia
Spinal Cord Injuries
Ion Channels
Hypoglycemia
Cations
Glutamic Acid
Cell Death
Stroke
Myocardial Infarction
Neurons
Membranes
Therapeutics
In Vitro Techniques

ASJC Scopus subject areas

  • General
  • Genetics

Cite this

Synthesis and characterization of a series of diarylguanidines that are noncompetitive N-methyl-D-aspartate receptor antagonists with neuroprotective properties. / Keana, J. F W; McBurney, R. N.; Scherz, M. W.; Fischer, J. B.; Hamilton, P. N.; Smith, Stephen; Server, A. C.; Finkbeiner, S.; Stevens, C. F.; Jahr, Craig; Weber, E.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 86, No. 14, 1989, p. 5631-5635.

Research output: Contribution to journalArticle

Keana, JFW, McBurney, RN, Scherz, MW, Fischer, JB, Hamilton, PN, Smith, S, Server, AC, Finkbeiner, S, Stevens, CF, Jahr, C & Weber, E 1989, 'Synthesis and characterization of a series of diarylguanidines that are noncompetitive N-methyl-D-aspartate receptor antagonists with neuroprotective properties', Proceedings of the National Academy of Sciences of the United States of America, vol. 86, no. 14, pp. 5631-5635.
Keana, J. F W ; McBurney, R. N. ; Scherz, M. W. ; Fischer, J. B. ; Hamilton, P. N. ; Smith, Stephen ; Server, A. C. ; Finkbeiner, S. ; Stevens, C. F. ; Jahr, Craig ; Weber, E. / Synthesis and characterization of a series of diarylguanidines that are noncompetitive N-methyl-D-aspartate receptor antagonists with neuroprotective properties. In: Proceedings of the National Academy of Sciences of the United States of America. 1989 ; Vol. 86, No. 14. pp. 5631-5635.
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