Disease relevance of Dilvax

• Ifenprodil, vincamine, and some related "anti-ischaemic" compounds are capable of increasing respiratory control in normal cerebral mitochondria, and this capacity might well help to explain their therapeutic potential in cerebrovascular disorders in which energy supply to the brain is limited [1].
• Under control conditions, ischemia produced an irreversible loss of the corticostriatal field potential amplitude, AP5, a competitive NMDA receptor antagonist, induced a slight rescue of the potential, while ifenprodil, a positive modulator of the proton sensor of the NMDA receptors, allowed a complete recovery from the ischemic insult [2].
• This compound potently protects cultured hippocampal neurons from glutamate toxicity (IC50 = 10 nM) while possessing little of the undesired alpha 1 adrenergic affinity (IC50 approximately 20 microM) of ifenprodil [3].
• Ifenprodil and SL 82.0715 as cerebral anti-ischemic agents. I. Evidence for efficacy in models of focal cerebral ischemia [4].
• In an identical protocol, a derivative of ifenprodil, SL 82.0715, reduced the volume of infarction in a manner comparable to that described for ifenprodil [4].

Psychiatry related information on Dilvax

• The NR2B KI mice exhibited normal locomotor activity making this ifenprodil-insensitive mouse model a valuable tool to test the specificity of NR2B selective antagonists in vivo [5].
• (2) Ifenprodil, an antagonist highly selective for NR2B subunit of the NMDA receptor, produced a dose-dependent reduction in CPP induced by morphine and novel environment, but not that by food consumption and social interaction [6].
• The effect of ifenprodil on pain threshold was prevented by naloxone [7].
• In the hot plate test, the intraperitoneal (i.p.) injection of ifenprodil significantly prolonged the reaction time of mice at the dose of 30 mg/kg, and increased the analgesic effect of morphine [7].
• Symptoms of patients suffering from somatoform disorders and ifenprodil [8].

High impact information on Dilvax

• We also show a similar interaction between the ifenprodil binding site and the glutamate binding site of NR1/NR2B receptors [9].
• We show that in receptors associating the NR2A-NTD (sensing nanomolar Zn) and the NR2B-NTD (sensing ifenprodil), each NTD binding site retains selective high affinity for its ligand [10].
• Death signaling likely originates from stimulation of extrasynaptic NR2B-subunit-containing NMDARs because it is accompanied by dephosphorylation of cAMP-response-element-binding protein (CREB) and it is inhibited by ifenprodil [11].
• In contrast, the NMDA-receptor current decay and sensitivity to the NMDA receptor 2B subunit-selective antagonist ifenprodil was affected strongly by such deprivation [12].
• Developmental changes in NMDA receptor glycine affinity and ifenprodil sensitivity reveal three distinct populations of NMDA receptors in individual rat cortical neurons [13].

Chemical compound and disease context of Dilvax

• Spermine toxicity was completely prevented by competitive (CGP 39551) and noncompetitive (MK-801) antagonists of the NMDA receptor, but was unaffected by a non-NMDA antagonist (NBQX) or by antagonists of the polyamine site present on the NMDA receptor complex, such as ifenprodil [14].
• Ro 25-6981 was found significantly more potent than amantadine and ifenprodil in reducing VCMs and tongue protrusions at all doses tested, and at the higher dose, it completely eliminated orofacial dyskinesia (p<0.05) [15].
• Conversely, pretreatment of DRG neurons from control animals with 100 microM sodium orthovanadate increased NMDAR currents and decreased ifenprodil sensitivity to levels similar to those observed in neurons from animals with colitis [16].
• Catalepsy in mice, induced by the administration of haloperidol (1 mg/kg), was inhibited by pretreatment with (+)-MK-801 (0.2 mg/kg) or ifenprodil (10 mg/kg) [17].
• Selective dysfunction of the vagal component of the baroreflex following cerebral ischemia: protection by ifenprodil and flunarizine [18].

Biological context of Dilvax

• NR1 down-regulation was inhibited by the general NMDAR antagonist DL-AP5 and also by ifenprodil, which specifically antagonizes NMDARs containing NR2B subunits [19].
• Low concentrations of ifenprodil were less effective after calcium-dependent inactivation of whole-cell currents, but the IC50 was unaffected, suggesting that calcium and ifenprodil act on a common set of channels [20].
• A regulatory domain (R1-R2) in the amino terminus of the N-methyl-D-aspartate receptor: effects of spermine, protons, and ifenprodil, and structural similarity to bacterial leucine/isoleucine/valine binding protein [21].
• 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 [22].
• However, it was reduced (by approximately 60 %) in the presence of 10 microM ifenprodil, to leave a residual NMDAR-mediated current that exhibited fast decay kinetics [23].

Anatomical context of Dilvax

• In oocytes voltage-clamped at -70 mV, ifenprodil inhibited NMDA-induced currents at NR1A/NR2B receptors with high affinity (IC50 = 0.34 microM) [22].
• High-affinity [3H]ifenprodil sites, defined either by ifenprodil displacement curves or by [3H]ifenprodil binding in the presence of 1 mM trifluoperazine, were concentrated in the cortex, hippocampus, striatum, and thalamus with little or no labeling of hindbrain or cerebellar regions [24].
• Ifenprodil reduced [3H]MK-801 binding under both equilibrium and nonequilibrium conditions, although the high-affinity component of inhibition described in membranes was not observed [25].
• In older pyramidal cells, the voltage dependence of the ifenprodil-insensitive component and the total INMDA were similar [26].
• In forebrain areas ifenprodil displaced [3H]ifenprodil (40 nM) in a biphasic manner with IC50 values ranging from 42 to 352 nM and 401 to 974 microM [24].

Associations of Dilvax with other chemical compounds

• These mutations did not affect the reversal potential, voltage-dependent block by extracellular Mg2+, block by ifenprodil, or stimulation by spermine at NR1/NR2B receptors [27].
• The GIRK currents induced by ethanol were also attenuated in the presence of ifenprodil [28].
• Haloperidol, trifluperidol, and ifenprodil inhibited the growth of Saccharomyces cerevisiae and reduced the ergosterol content of cells grown in their presence [29].
• The inhibitory effects of ifenprodil were not observed when ifenprodil was applied intracellularly, and were not affected by extracellular pH, which changed the proportion of the uncharged to protonated ifenprodil, suggesting its action from the extracellular side [28].
• The structure-activity relationship of the bis(phenylalkyl)amine series indicates that the piperidine ring and alkyl chain substitutions common to NR2B-selective antagonists such as ifenprodil, CP 101,606, and Ro 25-6981 are not necessary to generate potent and selective ligands [30].

Gene context of Dilvax

• Binding experiments with 125I-MK-801 implicated the region between amino acids 198 and 356 of NR2B for high affinity ifenprodil interaction [31].
• The effect of the NR2B antagonist ifenprodil was complex: 1 microm ifenprodil reduced open probability, while 10 microm reduced channel open time but had no effect on open probability of channels activated by 100 nm NMDA [32].
• No modulatory effect was observed on application of ifenprodil, confirming previous observations with rat NR1 + NR2A recombinant receptors [33].
• As expected of NR2D-containing receptors, these events were not affected by ifenprodil [23].
• As expected, the inhibition of whole cell currents by the NR2B-specific antagonist, ifenprodil, progressively decreased from 69.5 +/- 2.4% [6 days in vitro (DIV)] to 54.9 +/- 2.6% (8 DIV), before reaching a plateau in the second week (42.5 +/- 2%, 12-19 DIV) [34].

Analytical, diagnostic and therapeutic context of Dilvax

• However, the proportion of current blocked by low concentrations of ifenprodil was larger in outside-out patches than in whole-cell recordings, suggesting that intracellular factors may influence ifenprodil efficacy [20].
• The amplitude ratios of ifenprodil-sensitive components of NMDA response and D,L-2-amino-5-phosphovaleric acid (APV)-sensitive evoked postsynaptic current increased after axotomy [35].
• Ifenprodil antagonism increased after treatment for 24 h with KN93- and KN62-selective inhibitors of the Ca2+/calmodulin-dependent protein kinases (CaM kinases), indicating a selective increase of receptor containing NR2B subunit [36].
• Ifenprodil (0.3-3 mg/kg i.v.) administered as a perfusion over 3 hr after occlusion of the feline middle cerebral artery reduced the volume of infarcted tissue (measured 4 days after occlusion) in a dose-related manner [4].
• First, NMDA antagonism by ifenprodil and its derivative is an effective approach for tissue sparing in animal models of stroke and brain infarction [4].

References