Developmental Pb2+ exposure alters NMDAR subtypes and reduces CREB phosphorylation in the rat brain
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Ifenprodil
1. Ifenprodil is a selective, atypical non‐competitive antagonist of NMDA receptors that contain the NR2B subunit with an undefined mechanism of action. Ifenprodil is neuroprotective in in vivo models of cerebral ischaemia but lacks many of the undesirable side‐effects associated with NMDA antagonist. 2. Using whole‐cell voltage‐clamp recordings, we have studied the mechanism of inhibition of NMDA‐evoked currents by ifenprodil in rat cultured cortical neurones in the presence of saturating concentrations of glycine. 3. Ifenprodil antagonized NMDA receptors in an activity‐dependent manner, whilst also increasing the receptor affinity for glutamate recognition‐site agonists. Ifenprodil inhibition curves against 10 and 100 microM NMDA‐evoked currents yielded IC50 values of 0.88 and 0.17 microM, respectively. Thus, the apparent affinity of ifenprodil for the NMDA receptor is increased in an NMDA concentration‐dependent manner. 4. Currents evoked by 0.3 and 1 microM NMDA were potentiated to approximately 200% of control levels in the presence of 3 microM ifenprodil. Thus, with increasing concentration of NMDA the effect of ifenprodil on NMDA‐evoked currents changed from one of potentiation to one of increasing inhibition. 5. These results are predicted by a reaction scheme in which ifenprodil exhibits a 39‐ and 50‐fold higher affinity for the agonist‐bound activated and desensitized states of the NMDA receptor, respectively, relative to the resting, agonist‐unbound state. Furthermore, ifenprodil binding to the NMDA receptor results in a 6‐fold higher affinity for glutamate site agonists. 6. This represents a novel mechanism of NMDA receptor antagonism that, together with the subunit selectivity, probably contributes to the attractive neuropharmacological profile of this and related compounds.
Ifenprodil
Mechanism of Action
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In the late 1980s, a new class of N-methyl-D-aspartate (NMDA) receptor antagonists, exemplified by the phenylethanolamine ifenprodil (1), was identified. Initially, the mechanism of action of ifenprodil was a mystery as it was not a competitive antagonist at the glutamate or glycine (co-agonist) binding sites, nor was it a blocker of the calcium ion channel associated with the NMDA receptor. Early studies with a novel polyamine binding site associated with the NMDA receptor and functional studies in various brain regions suggested a unique and selective activity profile for 1. However, it was not until the NMDA receptor subunits were identified and expressed that ifenprodil was shown to be a selective antagonist for a subset of NMDA receptors containing the NR2B subunit. The wide range of potential therapeutic targets for NMDA antagonists coupled with the hope that NR2B selective agents might possess an improved clinical safety profile compared to non-selective compounds has supported an aggressive effort to develop the structure-activity relationships (SAR) of NR2B selective antagonists. This SAR and the basic physiology of the NMDA receptor form the basis of this review.
Ifenprodil
Competitive antagonist
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Abstract: In the late 1980s, a new class of N-methyl-D-aspartate (NMDA) receptor antagonists, exemplified by the phenylethanolamine ifenprodil (1), was identified. Initially, the mechanism of action of ifenprodil was a mystery as it was not a competitive antagonist at the glutamate or glycine (co-agonist) binding sites, nor was it a blocker of the calcium ion channel associated with the NMDA receptor. Early studies with a novel polyamine binding site associated with the NMDA receptor and functional studies in various brain regions suggested a unique and selective activity profile for 1. However, it was not until the NMDA receptor subunits were identified and expressed that ifenprodil was shown to be a selective antagonist for a subset of NMDA receptors containing the NR2B subunit. The wide range of potential therapeutic targets for NMDA antagonists coupled with the hope that NR2B selective agents might possess an improved clinical safety profile compared to non-selective compounds has supported an aggressive effort to develop the structure-activity relationships (SAR) of NR2B selective antagonists. This SAR and the basic physiology of the NMDA receptor form the basis of this review.
Ifenprodil
Competitive antagonist
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Ifenprodil
Polyamine
Dizocilpine
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Ifenprodil is a novel type of N-methyl-D-aspartate receptor antagonist: interaction with polyamines.
We have investigated the interactions of polyamines and the N-methyl-D-aspartate (NMDA) receptor antagonist ifenprodil with the binding of [3H]MK801 to the NMDA receptor. Spermine and spermidine but not putrescine substantially increase [3H]MK801 binding to well washed rat brain membranes in the absence or presence of saturating concentrations of glutamate and glycine. Spermine also increased the association and dissociation of [3H]MK801 from its binding site, suggesting that polyamines activate the NMDA receptor in a similar manner to glycine. Ifenprodil inhibited the binding of [3H]MK801 in a biphasic fashion. The high affinity phase of binding (Ki of approximately 15 nM) accounted for 50-60% of total [3H]MK801 binding in the nominal absence of glutamate, glycine, and polyamines or in the presence of 100 microM glutamate. This fraction was reduced to 20% by the addition of 30 microM glycine and could be abolished by the addition of 50 microM spermine. However, ifenprodil apparently did not act by binding to the polyamine recognition site. The low affinity phase (Ki of 20-40 microM) was insensitive to the presence of positive modulators and may represent binding to the Zn2+ regulatory site. Ifenprodil decreased NMDA and glycine-induced Ca2+ influx into cultured rat brain neurons. The potency of ifenprodil suggests that spermine may activate NMDA receptors in vivo. These data indicate that ifenprodil may bind to the NMDA receptor in a state-dependent fashion and preferentially stabilize an inactivated form of the channel.
Ifenprodil
Polyamine
Dizocilpine
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Abstract The subunit composition of N ‐methyl‐ d ‐aspartate (NMDA) receptors affects their function under normal and pathological conditions. Functional NMDA receptors are expressed in lower motor neurons, but their subunit composition has not been defined. Here, we employed electrophysiology, quantitative PCR, and immunohistochemistry to investigate the subunit composition of NMDA receptors in postnatal motor neurons of the Wistar rat facial nucleus (FN). Whole‐cell patch clamp recordings of acutely dissociated motor neurons from postnatal days 3 and 4 (P3–P4) showed that ifenprodil, a specific antagonist of the NMDA receptor 2B (NR2B) subunit, inhibited 91.62% ± 2.02% of NMDA‐induced current, whereas NVP‐AAM007, a specific antagonist of the NMDA receptor 2A (NR2A) subunit, inhibited much less of the current (16.69% ± 3.28%). Starting from P5, the inhibitory effects of ifenprodil and NVP‐AAM007 gradually decreased and increased, respectively, such that the effect of NVP‐AAM007 exceeded that of ifenprodil by P10. At P14, most of the NMDA‐induced current was inhibited by NVP‐AAM007 (84.59% ± 3.35%). Consistent with this, NR2B mRNA and protein were expressed highly at P3 and then gradually decreased by more than 75% by P14 in FN motor neurons, while NR1 was expressed stably over the same ages. However, NR2A mRNA and protein showed relatively constant levels between P3–P10 and decreased to 45% and 75% of the P3 level, respectively, by P14. Thus, analysis of functional NMDA receptors is critical to revealing subunit switching, which may be an important step in postnatal development of FN motor neurons.
Ifenprodil
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Ifenprodil
Excitotoxicity
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Ifenprodil has been widely used as an antagonist selective for NMDA receptors containing the NR2B subunit. Evidence suggests, however, that ifenprodil also increases NMDA receptor affinity. Using rat brain slices, we found that ifenprodil enhanced NMDA-induced current in both cortical and subcortical areas examined. To test whether the effect is due to an increase in NMDA receptor affinity, we compared the effect of ifenprodil on currents induced by different concentrations of NMDA. Consistent with the hypothesis, the enhancing effect (percent increase) was relatively constant at low NMDA concentrations. As NMDA concentration increased, however, the effect decreased. To test whether the effect is blocked when NMDA binding sites are saturated with NMDA, high concentrations of NMDA were applied. To partially block Ca(2+) influx and prevent cells from deteriorating, the experiments were performed in the presence of either MK801 or kynurenate, two noncompetitive antagonists. Under such conditions, ifenprodil not only failed to potentiate NMDA currents, but consistently suppressed the current. When the same concentration of NMDA was applied in the presence of the competitive antagonist CGP37849, ifenprodil regained its ability to potentiate NMDA currents. Furthermore, the higher the concentration of CGP37849 the more the NMDA current was potentiated by ifenprodil. These results, combined with previous studies, suggest that the enhancing effect is due to an increase in NMDA receptor affinity and is specific for responses induced by low NMDA concentrations. As NMDA concentration increases, the affinity-enhancing effect decreases. Consequently, the channel-suppressing effect becomes more prominent.
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Competitive antagonist
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Ifenprodil
Polyamine
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Ifenprodil is known to inhibit channel opening of NMDA receptors containing the NR2B subunit. However, it has also been shown to increase NMDA receptor affinity for glutamate-site agonists, including NMDA. The coexistence of the two opposing effects may explain why ifenprodil can either enhance or suppress an NMDA response depending on the level of NMDA binding and thus the NMDA concentration. Using whole cell recordings in rat prefrontal cortical slices, we report here that the effect of ifenprodil also depends on the speed and the direction of change of NMDA concentration. As shown previously, ifenprodil increased the inward current induced by low concentrations of NMDA applied through a local Y-tube perfusion system. However, the rising phase of the current was less enhanced compared to the falling phase. Increasing the speed of rising of NMDA concentration further reduced the enhancing effect of ifenprodil. When pressure ejection was used to produce even faster NMDA responses, the entire rising phase including the peak of the response was suppressed by ifenprodil, while the falling phase remained enhanced. These results are consistent with the suggestion that ifenprodil decreases both the association and dissociation rates of NMDA from NMDA receptors, and suggest that ifenprodil affects slow and fast NMDA responses in different manners. In particular, this study suggests that ifenprodil inhibits the rising phase of a fast NMDA response by suppressing both channel opening and the association of NMDA with NMDA receptors and that this inhibition can occur even when the level of NMDA binding is low. Synapse 39:313–318, 2001. © 2001 Wiley-Liss, Inc.
Ifenprodil
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