Flupirtine: A Review of Its Neuroprotective and Behavioral Properties

Schuster, G.; Schwarz, Michael; Block, F.; Pergande, G.; Schmidt, Werner

doi:10.1111/j.1527-3458.1998.tb00061.x

Cited by 19 publications

(24 citation statements)

References 33 publications

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“…11 Overall, in vitro, in vivo, and/or clinical trials have demonstrated protective properties in Alzheimer’s disease, Parkinson’s disease, epilepsy, Creutzfeldt–Jakob disease, glaucoma, age-related macular degeneration, ischemic stroke, prion disease, HIV related neuroinfection, multiple sclerosis, and Batten disease. 11,13–15 However, chronic use of 1 , as would be required to treat neurodegenerative diseases, may lead to mild hepatotoxicity that has led to restricted use in the European Union and precludes its use as a potential therapeutic for neurodegenerative disease. 16 …”

Section: Introductionmentioning

confidence: 99%

Discovery of Aromatic Carbamates that Confer Neuroprotective Activity by Enhancing Autophagy and Inducing the Anti-Apoptotic Protein B-Cell Lymphoma 2 (Bcl-2)

et al. 2017

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Neurodegenerative diseases share certain pathophysiological hallmarks that represent common targets for drug discovery. In particular, dysfunction of proteostasis and the resultant apoptotic death of neurons represent common pathways for pharmacological intervention. A library of aromatic carbamate derivatives based on the clinically available drug flupirtine was synthesized to determine a structure–activity relationship for neuroprotective activity. Several derivatives were identified that possess greater protective effect in human induced pluripotent stem cell-derived neurons, protecting up to 80% of neurons against etoposide-induced apoptosis at concentrations as low as 100 nM. The developed aromatic carbamates possess physicochemical properties desirable for CNS therapeutics. The primary known mechanisms of action of the parent scaffold are not responsible for the observed neuroprotective activity. Herein, we demonstrate that neuroprotective aromatic carbamates function to increase the Bcl-2/Bax ratio to an antiapoptotic state and activate autophagy through induction of beclin 1.

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Section: Introductionmentioning

confidence: 99%

Discovery of Aromatic Carbamates that Confer Neuroprotective Activity by Enhancing Autophagy and Inducing the Anti-Apoptotic Protein B-Cell Lymphoma 2 (Bcl-2)

et al. 2017

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“…For example, successful treatment of fibromyalgia has been reported (Stoll, 2000). In particular, the neuroprotective properties attributed to flupirtine are making it a possible candidate for treatment of Parkinson's and Alzheimer's diseases, Creutzfeldt-Jacob disease, and other neurodegenerative ailments (Schuster et al, 1998;Schröder and Müller, 2002;Otto et al, 2004).…”

mentioning

confidence: 99%

Investigation of the in Vitro Metabolism of the Analgesic Flupirtine

Methling¹,

Reszka²,

Lalk³

et al. 2008

Drug Metab Dispos

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ABSTRACT:The in vitro metabolism of flupirtine, ethyl-N-[2-amino-6-(4-fluorophenylmethyl-amino)pyridine-3-yl]carbamate, a centrally acting analgesic with muscle tone-reducing activity, was studied. Two flupirtine metabolites were already known: the N-acetylated analog D13223 and 4-fluorohippuric acid. The structure of flupirtine suggested that redox chemistry may play a role in metabolism, and cyclic voltammetry studies showed that the drug undergoes facile and irreversible redox reactions. Thus, oxidative metabolism was investigated first. With CYP3A1-induced rat liver microsomes an 18% turnover of flupirtine and a 20 to 25% turnover of D13223 took place over 30 min, but less than 5% turnover of flupirtine was observed with all human liver microsomal preparations tested, evidence that cytochrome P450 does not contribute appreciably to the metabolism in humans. Likewise, no involvement of human monoamine oxidase (isoforms A and B) was found for either flupirtine or D13223. In contrast, flupirtine was an excellent substrate for both human myeloperoxidase and horse radish peroxidase (HRP). These enzymes produced detectable amounts of oxidation products. Incubations of flupirtine with HRP produced an oxidation product that could be trapped with glutathione, the resulting glutathione conjugate was characterized by mass spectrometry and NMR. Metabolism of D13223 by both peroxidases was also observed but to a much lesser extent. Porcine liver esterases cleave the carbamate group of flupirtine, and both human N-acetyltransferases 1 and 2 acetylated the hydrolysis product, presumably descarboethoxyflupirtine, with nearly equal efficiencies to yield D13223. Incubations of human liver microsomes with flupirtine or the metabolite D13223 together with UDP-glucuronic acid gave two isomeric N-glucuronides in both cases.Flupirtine maleate (1) (ethyl-N-[2-amino-6-(4-fluoro-phenylmethylamino)pyridin-3-yl]carbamate maleate, Katadolon) (Scheme 1), a centrally acting nonopiate analgesic with muscle tone-reducing activity, does not show the classic side effects of opiates or nonsteroidal anti-inflammatory analgesics (Jakovlev et al., 1985;Szelenyi and Nickel, 1991). The drug has been effectively and safely used in Germany for 20 years. The mode of action is now mostly understood. Modification of prostaglandin formation is of minor importance for the analgesic action of flupirtine (Darius and Schrör, 1985). Evidence has accumulated that flupirtine interacts indirectly with the N-methyl-D-aspartate-responsive subtype of the glutamate receptor, possibly by opening K ϩ channels (Jakob and Krieglstein, 1997; Kornhuber et al., 1999a,b). Clinical interest in the compound is growing as further indications for the drug are found. For example, successful treatment of fibromyalgia has been reported (Stoll, 2000). In particular, the neuroprotective properties attributed to flupirtine are making it a possible candidate for treatment of Parkinson's and Alzheimer's diseases, Creutzfeldt-Jacob disease, and other neurodegenerative ailments (Schuste...

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“…Furthermore, flupirtine exerts anticonvulsant and antiepileptic effects (Schuster et al, 1998), as well as muscle relaxant activities in animals and humans (Timmann et al, 1995).…”

Section: Flupirtine a Functional Antagonist Of The Nmda Receptormentioning

confidence: 99%

“…The centrally acting non-opioid analgesic 2-amino-3-ethoxy-carbonylamino-6-4-fluoro-benzylamino-pyridine maleate (flupirtine), available under the trademark Katadolon | (ASTA Medica AWD GmbH, Germany), has been in clinical use since 1984 with a unique spectrum of pharmacological activities in pain states (Friedel and Fitton, 1993;Schuster et al, 1998) without exerting the typical side effects of therapeutically used opioids such as respiratory depression, constipation, tolerance or liability to cause addiction. Furthermore, flupirtine exerts anticonvulsant and antiepileptic effects (Schuster et al, 1998), as well as muscle relaxant activities in animals and humans (Timmann et al, 1995).…”

Section: Flupirtine a Functional Antagonist Of The Nmda Receptormentioning

confidence: 99%

The neuroprotectant properties of glutamate antagonists and antiglutamatergic drugs

Pedersen

Schmidt

2000

neurotox res

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In the slowly progressive neurodegenerative disorders like Parkinson's disease and Alzheimer's disease very different neuronal populations undergo degenerative processes, although the cascades of cellular events leading to death are supposed to be similar. We suggest that the complex pattern of degeneration in Parkinson's disease depends on two processes, a 'primary neurodegeneration' that takes place in the striato-nigral dopamine neurons and a 'secondary degeneration', occurring in distant structures of the basal ganglia network. For the purpose of explaining the regionally different expression of 'primary neurodegeneration' in different diseases, we postulate that the origin of neurodegeneration is associated with the local release of a neurotransmitter. For Parkinson's disease this would mean that the metabolism of dopamine in the striatum, nucleus accumbens and presumably the pedunculopontine tegmental nucleus, together with one or more pathological factors contribute to the initial neurodegeneration. There are recent studies indicating that a transneuronal retrograde degeneration of the substantia nigra pars compacta neurons might be induced by a loss of function of dopaminergic synapses in the striatum. We have recently established an animal model of retrograde striato-nigral degeneration, where the assessment of markers for cellular stress is possible. In Parkinson's disease, several structures distal from the substantia nigra pars compacta undergo neuropathological changes, characterizing the 'secondary neurodegeneration. Our recent studies provide experimental evidence for a chronic cellular stress in these structures because of a relative or absolute glutamatergic overactivity due to the initial loss of dopaminergic innervation. Thus, a loss of dopamine transforms the basal ganglia to a 'destructive network'. Both processes, the 'primary' and 'secondary neurodegeneration', affecting each other, characterize the progress of chronic neurodegeneration. From this point of view, we would further like to develop strategies for symptomatic amendment. Excitatory amino acids seem to be involved not only in the secondary processes of neurodegeneration, but also in initiation of the 'primary degeneration' of the substantia nigra pars compacta. Therefore, a reduction of glutamatergic overactivity constitutes a promising neuroprotective strategy. Especially the new antagonists of the NMDA-receptors with high affinity to the NR2B subunit of the receptor are in focus of our interest, since they reveal a favourable profile of side effects, therefore providing a promising tool for neuroprotection.

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Flupirtine: A Review of Its Neuroprotective and Behavioral Properties

Cited by 19 publications

References 33 publications

Discovery of Aromatic Carbamates that Confer Neuroprotective Activity by Enhancing Autophagy and Inducing the Anti-Apoptotic Protein B-Cell Lymphoma 2 (Bcl-2)

Discovery of Aromatic Carbamates that Confer Neuroprotective Activity by Enhancing Autophagy and Inducing the Anti-Apoptotic Protein B-Cell Lymphoma 2 (Bcl-2)

Investigation of the in Vitro Metabolism of the Analgesic Flupirtine

The neuroprotectant properties of glutamate antagonists and antiglutamatergic drugs

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