JPET Assistant Professor of Medicine (Clinician-Educator)

Home Help [Feedback] [For Subscribers] [Archive] [Search] [Contents]
QUICK SEARCH:   [advanced]


     

This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Parsons, C. G.
Right arrow Articles by Max. Headley, P.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Parsons, C. G.
Right arrow Articles by Max. Headley, P.

Vol. 283, Issue 3, 1264-1275, 1997

Novel Systemically Active Antagonists of the Glycine Site of the N-Methyl-D-aspartate Receptor: Electrophysiological, Biochemical and Behavioral Characterization

Chris G. Parsons, Wojciech Danysz, Günter Quack, Sabine Hartmann, Bianke Lorenz, Christine Wollenburg, Leokadia Baran, Edmund Przegalinski, Wojciech Kostowski, Pawel Krzascik, Boris Chizh and P. Max. Headley

Department of Pharmacology, Merz and Co., D-60318 Frankfurt am Main, Germany (C.G.P., W.D., G.Q., S.H., B.L., C.W.), Institute of Pharmacology PAN, Smetna 12, Cracow, Poland (L.B., E.P.), Department of Pharmacology, Institute of Psychiatry and Neurology, Sobieskiego 1-9, Warsaw, Poland (W.K., P.K.) and Department of Physiology, School of Medical Sciences, University Walk, Bristol BS8 1TD, England (B.C., P.M.H.)

A series of novel tricyclic pyrido-phthalazine-dione derivatives was tested for antagonistic effects at the strychnine-insensitive modulatory site of the N-methyl-D-aspartate (NMDA) receptor (glycineB). All compounds displaced [3H]MDL-105,519 binding to rat cortical membranes with IC50 values of between 90 nM and 3.6 µM. In patch-clamp experiments, steady-state inward current responses of cultured hippocampal neurons to NMDA (200 µM, glycine 1 µM) were antagonized by these same compounds with IC50 values of 0.14 to 13.8 µM. The antagonism observed was typical for glycineB antagonists, i.e., they induced desensitization and their effects were not use or voltage dependent. Moreover, increasing concentrations of glycine were able to decrease their apparent potency. Much higher concentrations (>100 µM) were required to antagonize alpha -amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid-induced currents. They were potent, systemically active NMDA receptor antagonists in vivo against responses of single neurons in the rat spinal cord to microelectrophoretic application of NMDA with ID50 values in the low milligram per kilogram i.v. range. They also inhibited pentylenetetrazol-, NMDA- and maximal electroshock-induced convulsions in mice with ED50 values ranging from 8 to 100 mg/kg i.p. The duration of anticonvulsive action was rather short but was prolonged by the organic acid transport inhibitor probenecid (200 mg/kg). The agents tested represent a novel class of systemically active glycineB antagonists with greatly improved bioavailability.

0022-3565/97/2833-1264$03.00/0
Copyright © 1997 by The American Society for Pharmacology and Experimental Therapeutics


This article has been cited by other articles:


Home page
 J. Biol. Chem.Home page
M. C. Barth, N. Ahluwalia, T. J. T. Anderson, G. J. Hardy, S. Sinha, J. A. Alvarez-Cardona, I. E. Pruitt, E. P. Rhee, R. A. Colvin, and R. E. Gerszten
Kynurenic Acid Triggers Firm Arrest of Leukocytes to Vascular Endothelium under Flow Conditions
J. Biol. Chem., July 17, 2009; 284(29): 19189 - 19195.
[Abstract] [Full Text] [PDF]

Home page
 J. Neurosci.Home page
M. Alkondon, E. F. R. Pereira, P. Yu, E. Z. Arruda, L. E. F. Almeida, P. Guidetti, W. P. Fawcett, M. T. Sapko, W. R. Randall, R. Schwarcz, et al.
Targeted Deletion of the Kynurenine Aminotransferase II Gene Reveals a Critical Role of Endogenous Kynurenic Acid in the Regulation of Synaptic Transmission via {alpha}7 Nicotinic Receptors in the Hippocampus
J. Neurosci., May 12, 2004; 24(19): 4635 - 4648.
[Abstract] [Full Text] [PDF]

Home page
 J. Neurosci.Home page
C. Hilmas, E. F. R. Pereira, M. Alkondon, A. Rassoulpour, R. Schwarcz, and E. X. Albuquerque
The Brain Metabolite Kynurenic Acid Inhibits {alpha}7 Nicotinic Receptor Activity and Increases Non-{alpha}7 Nicotinic Receptor Expression: Physiopathological Implications
J. Neurosci., October 1, 2001; 21(19): 7463 - 7473.
[Abstract] [Full Text] [PDF]

Home page
 Mol. Pharmacol.Home page
A. I. Sobolevsky, M. V. Yelshansky, and B. I. Khodorov
Eosine-Induced Blockade of N-Methyl-D-aspartate Channels in Acutely Isolated Rat Hippocampal Neurons
Mol. Pharmacol., February 1, 2000; 57(2): 334 - 341.
[Abstract] [Full Text]

Home page
 J. Pharmacol. Exp. Ther.Home page
M. B. Hesselink, H. Smolders, B. Eilbacher, A. G. De Boer, D. D. Breimer, and W. Danysz
The Role of Probenecid-Sensitive Organic Acid Transport in the Pharmacokinetics of N-Methyl-D-Aspartate Receptor Antagonists Acting at the GlycineB-Site: Microdialysis and Maximum Electroshock Seizures Studies
J. Pharmacol. Exp. Ther., August 1, 1999; 290(2): 543 - 550.
[Abstract] [Full Text]

Home page
 Pharmacol. Rev.Home page
R. Dingledine, K. Borges, D. Bowie, and S. F. Traynelis
The Glutamate Receptor Ion Channels
Pharmacol. Rev., March 1, 1999; 51(1): 7 - 62.
[Abstract] [Full Text] [PDF]

Home page
 Pharmacol. Rev.Home page
W. Danysz and C. G. Parsons
Glycine and N-Methyl-D-Aspartate Receptors: Physiological Significance and Possible Therapeutic Applications
Pharmacol. Rev., December 1, 1998; 50(4): 597 - 664.
[Abstract] [Full Text] [PDF]


Home Help [Feedback] [For Subscribers] [Archive] [Search] [Contents]
All ASPET Journals Molecular Pharmacology Pharmacological Reviews
Molecular Interventions Drug Metabolism and Disposition

Copyright © 1997 by the American Society for Pharmacology and Experimental Therapeutics.