A comparison of the anticonvulsant potency of (±) 2-amino-5-phosphono-pentanoic acid and (±) 2-amino-7-phosphonoheptanoic acid

Bs, Meldrum; Croucher, Martin J.; Czuczwar, S.J.; Collins, J.F.; Curry, Kenneth J.; Joseph, Mercy; Stone, T.W.

doi:10.1016/0306-4522(83)90281-6

Cited by 88 publications

(19 citation statements)

References 15 publications

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“…Although a number of studies clearly indicate that these competitive and noncompetitive antagonists are effective in experimental models of epilepsy and stroke (1 -3), clinical studies of these NMDA-receptor antagonists have proven unsuccessful (1 -3). Non-competitive inhibitors have produced serious behavioral effects (11,12) and have caused neuronal vacuolization (13) in some cases, while competitive inhibitors are often inactive in vivo because of poor transport to the brain (14,15). Since glycine acts as a co-transmitter at the NMDA receptor (1 -3), glycine antagonists, which may be associated with fewer side effects, have also been considered.…”

Section: Introductionmentioning

confidence: 99%

(1S,2R)-1-Phenyl-2-[(S)-1-aminopropyl]-N,N-diethylcyclopropane-carboxamide (PPDC), a New Class of NMDA-Receptor Antagonist: Molecular Design by a Novel Conformational Restriction Strategy

Shuto

Yoshii

Matsuda

2001

Japanese Journal of Pharmacology

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ABSTRACT-We have found that milnacipran, a clinically useful antidepressant due to its inhibition of the re-uptake of serotonin (5-HT) and noradrenaline, is also a non-competitive NMDA-receptor antagonist. Based on the cyclopropane structure of milnacipran, conformationally restricted analogs were designed and synthesized. Of these analogs, (1S,is 30-fold stronger than milnacipran as an NMDA-receptor antagonist with virtually no inhibitory effect on the neurotransmitter re-uptake. PPDC was identified as a new class of NMDA-receptor antagonist because it has a mode of action different from that of the previous antagonists; it selectivly binds the GluRe3/GluRz1 and GluRe4/GluRz l subtype receptors in an agonist-independent allosteric manner. Functional assays of PPDC with the Xenopus oocytes system and cultured mouse neurons under voltageclamp conditions confirmed that it acts as a potent NMDA-receptor antagonist. PPDC effectively protected against NMDA-induced neurotoxicity in both cultured mouse cerebral cortex and delayed neuronal death in a gerbil ischemic model. It was also active in a reserpine-treated mouse Parkinsons disease model. Thus, PPDC may be a candidate for a clinically useful NMDA-receptor antagonist, since the development of previous NMDA-receptor antagonists as drugs has been hindered by various undesirable side effects.

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Section: Introductionmentioning

confidence: 99%

(1S,2R)-1-Phenyl-2-[(S)-1-aminopropyl]-N,N-diethylcyclopropane-carboxamide (PPDC), a New Class of NMDA-Receptor Antagonist: Molecular Design by a Novel Conformational Restriction Strategy

Shuto

Yoshii

Matsuda

2001

Japanese Journal of Pharmacology

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“…DBN2 mice respond to a sound stimulus (1 10 dB for 60 sec) with sequential progression from a wild running phase to clonic, seizures to tonic extensions [Collins, 19721. As shown in Table 3, the rank order of anticonvulsant potency of competitive NMDA antagonists in this test is CPP = CGS 19755 > AP7 > AP.5 [Croucher et al, 1982;Meldrum et al, 1983;Chapman et al, 1Y87;Lehmann et al, 1987. Muscle relaxant effects are detected with doses slightly higher than those producing anticonvulsant effects, giving a therapeutic index of approximately 3 -4.5.…”

Section: A New Straight Chain Phosphonic Acid Derivative (Dl-(e)-2-mentioning

confidence: 96%

Excitatory amino acid antagonists: Behavioral and biochemical approaches for the development of new central nervous system therapeutic agents

Wilmot¹

1989

Drug Development Research

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171339-365, 1989. A general summary of behavioral and biochemical procedures that have been used for the evaluation of excitatory amino acid (EAA) antagonists, primarily those of the N-methyl-D-aspartate (NMDA) subtype, is presented. The effects of both competitive NMDA receptor antagonists and noncompetitive ion channel blockers are compared. In some tests, a specificity by 2-amino-5-phosphonovaleric acid (AP5), phencyclidine, and MK-801 for antagonism of NMDA receptors vs. other subtypes of EAA receptors has been demonstrated. Antagonists of the quisqualate or kainate subtypes of EAA receptor have been less well characterized.

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“…have been shown to be potent anticonvulsants in vivo (Croucher et al, 1982;Meldrum et al, 1983). Storcheim (1933) reported successful treatment of eight patients in status epilepticus by MgSO, injected intravenously (i.v.).…”

mentioning

confidence: 98%

Effects of Magnesium Sulfate on Pentylenetetrazol‐Induced Status Epilepticus

1991

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The use of magnesium sulfate (MgSO4) as an anticonvulsant is controversial. Status epilepticus was induced in 0.5% halothane-anesthetized Wistar rats with a threshold (90 mg/kg) or suprathreshold (200 mg/kg) dose of intravenous (i.v.) pentylenetetrazol (PTZ) under stereotactic hippocampal depth electrode monitoring. Fifteen minutes after seizure induction, the maximum hemodynamically tolerated dose of MgSO4 (10 mg/kg/min in 22 min) was administered i.v. MgSO4 was ineffective in altering seizure discharge. A subgroup of nine animals received hypertonic mannitol before MgSO4 to open the blood-brain barrier (BBB) to facilitate Mg2+ CNS penetration. Again MgSO4 was ineffective in attenuating epileptic activity. These results support the contention that MgSO4 is not an effective treatment for status epilepticus. We hypothesize that because Mg2+ blocks Ca2+ influx into the neuron through the N-methyl-D-aspartate (NMDA) receptor-operated calcium channel in a voltage-dependent manner it would be ineffective in neurons that are continuously depolarizing as in status epilepticus.

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A comparison of the anticonvulsant potency of (±) 2-amino-5-phosphono-pentanoic acid and (±) 2-amino-7-phosphonoheptanoic acid

Cited by 88 publications

References 15 publications

(1S,2R)-1-Phenyl-2-[(S)-1-aminopropyl]-N,N-diethylcyclopropane-carboxamide (PPDC), a New Class of NMDA-Receptor Antagonist: Molecular Design by a Novel Conformational Restriction Strategy

(1S,2R)-1-Phenyl-2-[(S)-1-aminopropyl]-N,N-diethylcyclopropane-carboxamide (PPDC), a New Class of NMDA-Receptor Antagonist: Molecular Design by a Novel Conformational Restriction Strategy

Excitatory amino acid antagonists: Behavioral and biochemical approaches for the development of new central nervous system therapeutic agents

Effects of Magnesium Sulfate on Pentylenetetrazol‐Induced Status Epilepticus

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