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Effects of ifenprodil on the N-methyl-D-aspartate receptor ionophore complex in rat brain.
Neurochem Int. 1992 Jul; 21(1):135-47.NI

Abstract

The effects of a cerebral anti-ischemic drug ifenprodil on the receptor ionophore complex of an N-methyl-D-aspartate (NMDA)-sensitive subclass of central excitatory amino acid receptors were examined using [3H](+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10- imine (MK-801) binding in rat brain synaptic membrane preparations as a biochemical measure. The binding in membrane preparations not extensively washed was markedly inhibited not only by competitive NMDA antagonists such as (+/-)-3-(2-carboxypiperazin-4-yl)propyl-1-phosphonic, D-2-amino-5-phosphonovaleric and D-2-amino-7-phosphonoheptanoic acids, but also by competitive antagonists at the strychnine-insensitive glycine (Gly) site including 7-chlorokynurenic acid and 6,7-dichloroquinoxaline-2,3-dione. Among several proposed ligands for alpha-adrenergic receptors tested, ifenprodil most potently inhibited the binding in these membrane preparations due to a decrease in the density of the binding sites without significantly affecting the affinity. Ifenprodil also inhibited the binding of [3H]N-[1-(2-thienyl)cyclohexyl]piperidine as well as of [3H]MK-801 to open NMDA channels in a concentration-dependent manner at concentrations above 10 nM in membrane preparations extensively washed but not treated by a detergent, with a Hill coefficient of less than unity. Further treatment of extensively washed membrane preparations with a low concentration of Triton X-100 resulted in an almost complete abolition of [3H]MK-801 binding, and the binding was restored to the level found in membrane preparations not extensively washed following the addition of both L-glutamic acid (Glu) and Gly. Ifenprodil was effective in inhibiting [3H]MK-801 binding via reducing both initial association and dissociation rates in Triton-treated membrane preparations, irrespective of the presence of Glu and Gly added. The binding in Triton-treated membrane preparations was additionally potentiated by the polyamine spermidine in a concentration-dependent manner at concentrations above 10 microM in the presence of both Glu and Gly at maximally effective concentrations. Ifenprodil invariably diminished the abilities of these three stimulants to potentiate [3H]MK-801 binding at concentrations over 1 microM in a manner that the maximal responses each were reduced. These results suggest that ifenprodil does not interfere with the NMDA receptor complex as a specific isosteric antagonist at the polyamine domain in contrast to the prevailing view.

Authors+Show Affiliations

Department of Pharmacology, Setsunan University, Osaka, Japan.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

1363860

Citation

Ogita, K, et al. "Effects of Ifenprodil On the N-methyl-D-aspartate Receptor Ionophore Complex in Rat Brain." Neurochemistry International, vol. 21, no. 1, 1992, pp. 135-47.
Ogita K, Ohkawara A, Suzuki T, et al. Effects of ifenprodil on the N-methyl-D-aspartate receptor ionophore complex in rat brain. Neurochem Int. 1992;21(1):135-47.
Ogita, K., Ohkawara, A., Suzuki, T., Ohgaki, T., Uchida, S., Meguri, H., & Yoneda, Y. (1992). Effects of ifenprodil on the N-methyl-D-aspartate receptor ionophore complex in rat brain. Neurochemistry International, 21(1), 135-47.
Ogita K, et al. Effects of Ifenprodil On the N-methyl-D-aspartate Receptor Ionophore Complex in Rat Brain. Neurochem Int. 1992;21(1):135-47. PubMed PMID: 1363860.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Effects of ifenprodil on the N-methyl-D-aspartate receptor ionophore complex in rat brain. AU - Ogita,K, AU - Ohkawara,A, AU - Suzuki,T, AU - Ohgaki,T, AU - Uchida,S, AU - Meguri,H, AU - Yoneda,Y, PY - 1992/7/1/pubmed PY - 1992/7/1/medline PY - 1992/7/1/entrez SP - 135 EP - 47 JF - Neurochemistry international JO - Neurochem Int VL - 21 IS - 1 N2 - The effects of a cerebral anti-ischemic drug ifenprodil on the receptor ionophore complex of an N-methyl-D-aspartate (NMDA)-sensitive subclass of central excitatory amino acid receptors were examined using [3H](+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10- imine (MK-801) binding in rat brain synaptic membrane preparations as a biochemical measure. The binding in membrane preparations not extensively washed was markedly inhibited not only by competitive NMDA antagonists such as (+/-)-3-(2-carboxypiperazin-4-yl)propyl-1-phosphonic, D-2-amino-5-phosphonovaleric and D-2-amino-7-phosphonoheptanoic acids, but also by competitive antagonists at the strychnine-insensitive glycine (Gly) site including 7-chlorokynurenic acid and 6,7-dichloroquinoxaline-2,3-dione. Among several proposed ligands for alpha-adrenergic receptors tested, ifenprodil most potently inhibited the binding in these membrane preparations due to a decrease in the density of the binding sites without significantly affecting the affinity. Ifenprodil also inhibited the binding of [3H]N-[1-(2-thienyl)cyclohexyl]piperidine as well as of [3H]MK-801 to open NMDA channels in a concentration-dependent manner at concentrations above 10 nM in membrane preparations extensively washed but not treated by a detergent, with a Hill coefficient of less than unity. Further treatment of extensively washed membrane preparations with a low concentration of Triton X-100 resulted in an almost complete abolition of [3H]MK-801 binding, and the binding was restored to the level found in membrane preparations not extensively washed following the addition of both L-glutamic acid (Glu) and Gly. Ifenprodil was effective in inhibiting [3H]MK-801 binding via reducing both initial association and dissociation rates in Triton-treated membrane preparations, irrespective of the presence of Glu and Gly added. The binding in Triton-treated membrane preparations was additionally potentiated by the polyamine spermidine in a concentration-dependent manner at concentrations above 10 microM in the presence of both Glu and Gly at maximally effective concentrations. Ifenprodil invariably diminished the abilities of these three stimulants to potentiate [3H]MK-801 binding at concentrations over 1 microM in a manner that the maximal responses each were reduced. These results suggest that ifenprodil does not interfere with the NMDA receptor complex as a specific isosteric antagonist at the polyamine domain in contrast to the prevailing view. SN - 0197-0186 UR - https://www.unboundmedicine.com/medline/citation/1363860/Effects_of_ifenprodil_on_the_N_methyl_D_aspartate_receptor_ionophore_complex_in_rat_brain_ DB - PRIME DP - Unbound Medicine ER -