Orphenadrine is an uncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist: binding and patch clamp studies

  title={Orphenadrine is an uncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist: binding and patch clamp studies},
  author={Johannes Kornhuber and Chris G. Parsons and S. Hartmann and Wolfgang Retz and S. Kamolz and Johannes Thome and Peter Franz Riederer},
  journal={Journal of Neural Transmission / General Section JNT},
Orphenadrine has been used as an antiparkinsonian, antispastic and analgesic drug for many years. Here we show that orphenadrine inhibits [3H]MK-801 binding to the phencyclidine (PCP) binding site of the N-methyl-D-aspartate (NMDA)-receptor in homogenates of postmortem human frontal cortex with a Ki-value of 6.0 ± 0.7 μM. The NMDA receptor antagonistic effects of orphenadrine were assessed using concentration- and patch-clamp techniques on cultured superior colliculus neurones. Orphenadrine… 

Anticholinergic antiparkinson drug orphenadrine inhibits HERG channels: block attenuation by mutations of the pore residues Y652 or F656

It is shown that the anticholinergic agent orphenadrine is an antagonist at HERG channels, providing a novel molecular basis for the reported proarrhythmic side effects of or phenadrine.

Evaluation of the phencyclidine-like discriminative stimulus effects of novel NMDA channel blockers in rats

The results demonstrate that the cellular actions of the individual channel-blocking NMDA antagonists, in particular affinity for the channel site and NMDA receptor specificity, are important determinants of their discriminative stimulus effects.

Nefopam inhibits calcium influx, cGMP formation, and NMDA receptor-dependent neurotoxicity following activation of voltage sensitive calcium channels

The novel action of nefopam may be important both for its central analgesic effects and for its potential therapeutic use in neurological and neuropsychiatric disorders involving an excessive glutamate release.

Neuronal sensitization and its behavioral correlates in a rat model of neuropathy are prevented by a cyclic analog of orphenadrine.

It is proposed that nefopam exerts a preventive analgesic effect, with a possible role in modulating NMDA receptor-mediated effects in central sensitization.

Nefopam is more potent than carbamazepine for neuroprotection against veratridine in vitro and has anticonvulsant properties against both electrical and chemical stimulation

In vivo, NEF was significantly more effective than CBZ in preventing MES, although both drugs were equally effective against MES-induced TC, and nefopam provided protection against isoniazid-induced seizures at doses similar to those protecting against Mes.

Anticholinergic drugs rescue synaptic plasticity in DYT1 dystonia: Role of M1 muscarinic receptors

It is demonstrated that selective M1 muscarinic receptor antagonism offsets synaptic plasticity deficits in the striatum of mice with the DYT1 dystonia mutation, providing a potential mechanistic rationale for the development of improved antimuscarinic therapies for this movement disorder.



The antiparkinsonian agent budipine is an N-methyl-D-aspartate antagonist

It is concluded that the newly discovered NMDA antagonistic action of budipine is at least partly responsible for its antiparkinsonian activity and is additional evidence for the hypothesis that NMDA antagonists may be useful in the treatment of Parkinson's disease.

Open-channel block of N-methyl-D-aspartate (NMDA) responses by memantine: therapeutic advantage against NMDA receptor-mediated neurotoxicity

  • H. ChenJ. Pellegrini S. Lipton
  • Biology, Psychology
    The Journal of neuroscience : the official journal of the Society for Neuroscience
  • 1992
Low micromolar concentrations of memantine, levels known to be tolerated by patients receiving the drug for the treatment of Parkinson's disease, prevent NMDA receptor-mediated neurotoxicity in cultures of rat cortical and retinal ganglion cell neurons; memantine also appears to be both safe and effective in a rat stroke model, suggesting that memantine has considerable therapeutic potential for the myriad of clinical entities associated with NMda receptor- mediated neurotoxicity.

Inhibitory effects of the antiparkinsonian drugs memantine and amantadine on N-methyl-D-aspartate-evoked acetylcholine release in the rabbit caudate nucleus in vitro.

It is concluded that, by antagonizing NMDA receptor-mediated ACh release, memantine and amantadine may act as functional "anticholinergics" when administered clinically to treat Parkinson's disease.

Are NMDA antagonistic properties relevant for antiparkinsonianlike activity in rats?—Case of amantadine and memantine

It can be assumed that the doses of amantadine, memantine and MK-801 showing antiparkinsonian-like activity in animals result in plasma levels leading to NMDA antagonism, but in the haloperidol-induced catalepsy test the efficacy of amanadine was higher than memantine, while the opposite was true for rotation and reserpine-induced sedation indicating pharmacodynamic differences between both agents.

Effects of antiparkinsonian drugs on muscarinic receptor binding in rat brain, heart and lung.

The results confirm the high affinity of most of the antiparkinsonian drugs for brain muscarinic receptors, and the dissociation constants agree with the average clinical doses of the drugs.

Amantadine and memantine are NMDA receptor antagonists with neuroprotective properties.

Neuroprotection targeting glutamate receptors does apparently not have to be associated with prominent psychotogenicity, and the development and evaluation of new neuroprotective drugs will have to performed in consideration both of the relative safety and of the good clinical effect of the already known and established aminoadamantanes.

Heteromeric NMDA Receptors: Molecular and Functional Distinction of Subtypes

Molecular cloning identified three complementary DNA species of rat brain, encoding NMDA receptor subunits NMDAR2A (NR2A), NR2B, and NR2C, which are 55 to 70% ientical in sequence, and these are structurally related, with less than 20% sequence identity, to other excitatory amino acid receptor sub Units.