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Novel systemically active antagonists of the glycine site of the N-methyl-D-aspartate receptor: electrophysiological, biochemical and behavioral characterization.
J Pharmacol Exp Ther. 1997 Dec; 283(3):1264-75.JP

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 microM. In patch-clamp experiments, steady-state inward current responses of cultured hippocampal neurons to NMDA (200 microM, glycine 1 microM) were antagonized by these same compounds with IC50 values of 0.14 to 13.8 microM. 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 microM) 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.

Authors+Show Affiliations

Department of Pharmacology, Merz and Co., D-60318 Frankfurt am Main, Germany.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article

Language

eng

PubMed ID

9400002

Citation

Parsons, C G., et al. "Novel Systemically Active Antagonists of the Glycine Site of the N-methyl-D-aspartate Receptor: Electrophysiological, Biochemical and Behavioral Characterization." The Journal of Pharmacology and Experimental Therapeutics, vol. 283, no. 3, 1997, pp. 1264-75.
Parsons CG, Danysz W, Quack G, et al. Novel systemically active antagonists of the glycine site of the N-methyl-D-aspartate receptor: electrophysiological, biochemical and behavioral characterization. J Pharmacol Exp Ther. 1997;283(3):1264-75.
Parsons, C. G., Danysz, W., Quack, G., Hartmann, S., Lorenz, B., Wollenburg, C., Baran, L., Przegalinski, E., Kostowski, W., Krzascik, P., Chizh, B., & Headley, P. M. (1997). Novel systemically active antagonists of the glycine site of the N-methyl-D-aspartate receptor: electrophysiological, biochemical and behavioral characterization. The Journal of Pharmacology and Experimental Therapeutics, 283(3), 1264-75.
Parsons CG, et al. Novel Systemically Active Antagonists of the Glycine Site of the N-methyl-D-aspartate Receptor: Electrophysiological, Biochemical and Behavioral Characterization. J Pharmacol Exp Ther. 1997;283(3):1264-75. PubMed PMID: 9400002.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Novel systemically active antagonists of the glycine site of the N-methyl-D-aspartate receptor: electrophysiological, biochemical and behavioral characterization. AU - Parsons,C G, AU - Danysz,W, AU - Quack,G, AU - Hartmann,S, AU - Lorenz,B, AU - Wollenburg,C, AU - Baran,L, AU - Przegalinski,E, AU - Kostowski,W, AU - Krzascik,P, AU - Chizh,B, AU - Headley,P M, PY - 1998/2/12/pubmed PY - 1998/2/12/medline PY - 1998/2/12/entrez SP - 1264 EP - 75 JF - The Journal of pharmacology and experimental therapeutics JO - J Pharmacol Exp Ther VL - 283 IS - 3 N2 - 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 microM. In patch-clamp experiments, steady-state inward current responses of cultured hippocampal neurons to NMDA (200 microM, glycine 1 microM) were antagonized by these same compounds with IC50 values of 0.14 to 13.8 microM. 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 microM) 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. SN - 0022-3565 UR - https://www.unboundmedicine.com/medline/citation/9400002/Novel_systemically_active_antagonists_of_the_glycine_site_of_the_N_methyl_D_aspartate_receptor:_electrophysiological_biochemical_and_behavioral_characterization_ L2 - https://jpet.aspetjournals.org/cgi/pmidlookup?view=long&pmid=9400002 DB - PRIME DP - Unbound Medicine ER -