Antagonists Selective for NMDA Receptors Containing the NR2B Subunit
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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.Keywords:
Ifenprodil
Competitive antagonist
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
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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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Ifenprodil
Polyamine
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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The experiments examined the ability of competitive N-methyl-D-aspartate (NMDA) antagonists (CPP, CGS 19755), noncompetitive NMDA antagonists [phencyclidine (PCP), ketamine, MK-801], other putative excitatory amino acid antagonists (ifenprodil, PK 26124), and anticonvulsants (pentobarbital, chlordiazepoxide) to antagonize the discriminative stimulus (DS) effects of NMDA and to produce PCP-like DS effects. Rats were trained to discriminate NMDA (40 mg/kg) from saline. The DS effects of NMDA were blocked by the competitive NMDA antagonists but were antagonized at best partially by the other drugs tested. The response rate decreasing effects of NMDA were attenuated to varied extents by both the competitive and the noncompetitive NMDA antagonists. Some competitive and noncompetitive NMDA antagonists partially mimicked NMDA. To further examine their NMDA-antagonist properties, the compounds were also tested for antagonism of NMDA (160 mg/kg)-induced lethality in mice; only the competitive and noncompetitive NMDA antagonists completely protected against NMDA-induced lethality. In rats discriminating PCP (2.5 mg/kg) from saline, the competitive NMDA antagonists produced less drug-appropriate responding than the noncompetitive NMDA antagonists but more than was produced by the other drugs tested. The extent to which compounds antagonize behavioral effects of NMDA and produce PCP-like DS effects may depend partly on the effect measured and on the component of the NMDA receptor complex with which they interact. Although the competitive NMDA antagonists were more effective in blocking NMDA than the other drugs tested, they failed to act as pure antagonists of the DS effects of NMDA.
Phencyclidine
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Ifenprodil
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Dizocilpine
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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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Neu2000 [NEU, 2-hydroxy-5-(2,3,5,6-tetrafluoro-4-trifluoromethyl-benzylamino)-benzoic acid], a derivative of sulfasalazine, attenuates NMDA-induced neuronal toxicity. Here we investigated the effects of NEU on the NMDA receptor (NMDAR) using whole-cell patch clamp technique to determine the molecular mechanisms underlying its neuroprotective role. NEU reversibly suppressed NMDA responses in an uncompetitive manner with fast binding kinetics. Its inhibition of NMDAR activity depended on both the concentration and the use of agonist but not on the membrane potential. NEU accelerated NMDA desensitization without affecting the binding affinity of NMDAR for its agonists and stabilized the closed state of NMDAR. Therefore, NEU should effectively alleviate disorders that are a result of glutamate excitoxicity with fewer side effects because it is a low-affinity gating modifier that antagonizes NMDAR in an uncompetitive manner. Moreover, in the presence of ifenprodil (an NR2B antagonist) but not NVP-AAM077 [(R)-[(S)-1-(4-bromo-phenyl)-ethylamino]-(2,3-dioxo-1,2,3,4-tetrahydro-quinoxalin-5-yl)-methyl]-phosphonic acid, an NR2A antagonist], the extent of NEU block was decreased, suggesting that NEU is an NR2B-specific antagonist.
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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.
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Ifenprodil
Phencyclidine
Dizocilpine
Memantine
Competitive antagonist
Psychotomimetic
Sigma receptor
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