Tags

Type your tag names separated by a space and hit enter

Ifenprodil discriminates subtypes of the N-methyl-D-aspartate receptor: selectivity and mechanisms at recombinant heteromeric receptors.
Mol Pharmacol. 1993 Oct; 44(4):851-9.MP

Abstract

The effects of the atypical N-methyl-D-aspartate (NMDA) receptor antagonist ifenprodil were investigated by voltage-clamp recording of Xenopus oocytes expressing heteromeric NMDA receptors from cloned NR1 and NR2 subunit RNAs. In oocytes voltage-clamped at -70 mV, ifenprodil inhibited NMDA-induced currents at NR1A/NR2B receptors with high affinity (IC50 = 0.34 microM). The affinity of NR1A/NR2A receptors for ifenprodil (IC50 = 146 microM) was 400-fold lower than that of NR1A/NR2B receptors. The rate of onset of inhibition by low concentrations of ifenprodil acting at NR1A/NR2B receptors was considerably slower than the onset of inhibition seen with high concentrations of ifenprodil acting at NR1A/NR2A receptors. The onset and recovery of blockade by ifenprodil at NR1A/NR2B receptors were not activity dependent. The inhibitory effects of low concentrations of ifenprodil at NR1A/NR2B receptors were not voltage dependent. In contrast, the inhibitory effects of high concentrations of ifenprodil at NR1A/NR2A receptors were partially voltage dependent, and a greater inhibition of NMDA-induced currents was seen at hyperpolarized membrane potentials than at depolarized membrane potentials. The reversal potential of NMDA currents was not altered in the presence of ifenprodil. Ifenprodil may act as a weak open-channel blocker of NR1A/NR2A receptors. The degree of inhibition seen with 100 microM ifenprodil at NR1A/NR2A receptors was not altered by changes in the concentration of extracellular glycine. However, the inhibitory effect of 1 microM ifenprodil at NR1A/NR2B receptors was reduced by increasing the concentration of glycine. Thus, part of the mechanism of action of ifenprodil at NR1A/NR2B receptors may involve noncompetitive antagonism of the effects of glycine. These results indicate that the mechanism of action of ifenprodil, as well as the potency of this antagonist, is different at NR1A/NR2B and NR1A/NR2A receptors expressed in Xenopus oocytes.

Authors+Show Affiliations

Department of Pharmacology, University of Pennsylvania School of Medicine, Philadelphia 19104-6084.

Pub Type(s)

Journal Article
Research Support, U.S. Gov't, P.H.S.

Language

eng

PubMed ID

7901753

Citation

Williams, K. "Ifenprodil Discriminates Subtypes of the N-methyl-D-aspartate Receptor: Selectivity and Mechanisms at Recombinant Heteromeric Receptors." Molecular Pharmacology, vol. 44, no. 4, 1993, pp. 851-9.
Williams K. Ifenprodil discriminates subtypes of the N-methyl-D-aspartate receptor: selectivity and mechanisms at recombinant heteromeric receptors. Mol Pharmacol. 1993;44(4):851-9.
Williams, K. (1993). Ifenprodil discriminates subtypes of the N-methyl-D-aspartate receptor: selectivity and mechanisms at recombinant heteromeric receptors. Molecular Pharmacology, 44(4), 851-9.
Williams K. Ifenprodil Discriminates Subtypes of the N-methyl-D-aspartate Receptor: Selectivity and Mechanisms at Recombinant Heteromeric Receptors. Mol Pharmacol. 1993;44(4):851-9. PubMed PMID: 7901753.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Ifenprodil discriminates subtypes of the N-methyl-D-aspartate receptor: selectivity and mechanisms at recombinant heteromeric receptors. A1 - Williams,K, PY - 1993/10/1/pubmed PY - 1993/10/1/medline PY - 1993/10/1/entrez SP - 851 EP - 9 JF - Molecular pharmacology JO - Mol Pharmacol VL - 44 IS - 4 N2 - The effects of the atypical N-methyl-D-aspartate (NMDA) receptor antagonist ifenprodil were investigated by voltage-clamp recording of Xenopus oocytes expressing heteromeric NMDA receptors from cloned NR1 and NR2 subunit RNAs. In oocytes voltage-clamped at -70 mV, ifenprodil inhibited NMDA-induced currents at NR1A/NR2B receptors with high affinity (IC50 = 0.34 microM). The affinity of NR1A/NR2A receptors for ifenprodil (IC50 = 146 microM) was 400-fold lower than that of NR1A/NR2B receptors. The rate of onset of inhibition by low concentrations of ifenprodil acting at NR1A/NR2B receptors was considerably slower than the onset of inhibition seen with high concentrations of ifenprodil acting at NR1A/NR2A receptors. The onset and recovery of blockade by ifenprodil at NR1A/NR2B receptors were not activity dependent. The inhibitory effects of low concentrations of ifenprodil at NR1A/NR2B receptors were not voltage dependent. In contrast, the inhibitory effects of high concentrations of ifenprodil at NR1A/NR2A receptors were partially voltage dependent, and a greater inhibition of NMDA-induced currents was seen at hyperpolarized membrane potentials than at depolarized membrane potentials. The reversal potential of NMDA currents was not altered in the presence of ifenprodil. Ifenprodil may act as a weak open-channel blocker of NR1A/NR2A receptors. The degree of inhibition seen with 100 microM ifenprodil at NR1A/NR2A receptors was not altered by changes in the concentration of extracellular glycine. However, the inhibitory effect of 1 microM ifenprodil at NR1A/NR2B receptors was reduced by increasing the concentration of glycine. Thus, part of the mechanism of action of ifenprodil at NR1A/NR2B receptors may involve noncompetitive antagonism of the effects of glycine. These results indicate that the mechanism of action of ifenprodil, as well as the potency of this antagonist, is different at NR1A/NR2B and NR1A/NR2A receptors expressed in Xenopus oocytes. SN - 0026-895X UR - https://www.unboundmedicine.com/medline/citation/7901753/Ifenprodil_discriminates_subtypes_of_the_N_methyl_D_aspartate_receptor:_selectivity_and_mechanisms_at_recombinant_heteromeric_receptors_ L2 - http://molpharm.aspetjournals.org/cgi/pmidlookup?view=long&pmid=7901753 DB - PRIME DP - Unbound Medicine ER -