Novel Systemically Active Antagonists of the Glycine Site of the N-Methyl-d-aspartate Receptor: Electrophysiological, Biochemical and Behavioral Characterization
- Chris G. Parsons1,
- Wojciech Danysz1,
- Günter Quack1,
- Sabine Hartmann1,
- Bianke Lorenz1,
- Christine Wollenburg1,
- Leokadia Baran2,
- Edmund Przegalinski2,
- Wojciech Kostowski3,
- Pawel Krzascik3,
- Boris Chizh4 and
- P. Max. Headley4
- 1Department of Pharmacology, Merz and Co., D-60318 Frankfurt am Main, Germany (C.G.P., W.D., G.Q., S.H., B.L., C.W.), 2Institute of Pharmacology PAN, Smetna 12, Cracow, Poland (L.B., E.P.), 3Department of Pharmacology, Institute of Psychiatry and Neurology, Sobieskiego 1–9, Warsaw, Poland (W.K., P.K.) and 4Department of Physiology, School of Medical Sciences, University Walk, Bristol BS8 1TD, England (B.C., P.M.H.)
Abstract
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 glycineBantagonists, 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 α-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.
Footnotes
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Send reprint requests to: Dr. Chris. G. Parsons, Dept. of Pharmacology, Merz & Co., Eckenheimer Landstrasse 100–104, D-60318 Frankfurt am Main, Germany.
- Abbreviations:
- AMPA
- α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid
- CNS
- central nervous system
- DH
- dorsal horn
- GABA
- γ-aminobutyric acid
- GlycineB
- strychnine-insensitive, co-agonistic glycine site of the NMDA receptor
- MES
- maximal electroshock
- NMDA
- N-methyl-d-aspartate
- PTZ
- pentylenetetrazol
- TI
- therapeutic index
- 5
- 7-DCKA, 5,7-dichlorokynurenic acid
- HEPES
- N-2-hydroxyethylpiperazine-N′-2-ethanesulfonic acid
- ACPC
- 1-aminocyclopropanecarboxylic acid
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- Received April 8, 1997.
- Accepted July 30, 1997.
- The American Society for Pharmacology and Experimental Therapeutics
