Tonabersat (SB‐220453) a novel benzopyran with anticonvulsant properties attenuates trigeminal nerve‐induced neurovascular reflexes

Parsons, Andrew A.; Bingham, Sharon; Raval, Pravin; Read, Simon; Thompson, Mervyn; Upton, Neil

doi:10.1038/sj.bjp.0703932

Cited by 50 publications

(33 citation statements)

References 46 publications

(78 reference statements)

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“…418 The novel benzoylamino benzopyran tonabersat [SB-220453; an analog of the anticonvulsant carabersat (SB-204269) 419 ], which is currently in clinical development for migraine, is believed to block gap junctions. 420 …”

Section: Gap Junctions (Connexins)mentioning

confidence: 99%

Molecular Targets for Antiepileptic Drug Development

2007

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Summary:This review considers how recent advances in the physiology of ion channels and other potential molecular targets, in conjunction with new information on the genetics of idiopathic epilepsies, can be applied to the search for improved antiepileptic drugs (AEDs). Marketed AEDs predominantly target voltage-gated cation channels (the ␣ subunits of voltagegated Na ϩ channels and also T-type voltage-gated Ca 2ϩ channels) or influence GABA-mediated inhibition. Recently, ␣2-␦ voltage-gated Ca 2ϩ channel subunits and the SV2A synaptic vesicle protein have been recognized as likely targets. Genetic studies of familial idiopathic epilepsies have identified numerous genes associated with diverse epilepsy syndromes, including genes encoding Na ϩ channels and GABA A receptors, which are known AED targets. A strategy based on genes associated with epilepsy in animal models and humans suggests other potential AED targets, including various voltage-gated Ca 2ϩ channel subunits and auxiliary proteins, A-or M-type voltage-gated K ϩ channels, and ionotropic glutamate receptors. Recent progress in ion channel research brought about by molecular cloning of the channel subunit proteins and studies in epilepsy models suggest additional targets, including G-protein-coupled receptors, such as GABA B and metabotropic glutamate receptors; hyperpolarization-activated cyclic nucleotide-gated cation (HCN) channel subunits, responsible for hyperpolarization-activated current I h ; connexins, which make up gap junctions; and neurotransmitter transporters, particularly plasma membrane and vesicular transporters for GABA and glutamate. New information from the structural characterization of ion channels, along with better understanding of ion channel function, may allow for more selective targeting. For example, Na ϩ channels underlying persistent Na ϩ currents or GABA A receptor isoforms responsible for tonic (extrasynaptic) currents represent attractive targets. The growing understanding of the pathophysiology of epilepsy and the structural and functional characterization of the molecular targets provide many opportunities to create improved epilepsy therapies.

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Section: Gap Junctions (Connexins)mentioning

confidence: 99%

Molecular Targets for Antiepileptic Drug Development

2007

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“…It seems to have no contractile effect on isolated vessels or myocardium [54], but it inhibits trigeminally mediated parasympathetic reflexes on carotid vasculature [55]. A RCDBT [56] on glyceryl-trinitrate (GTN)-induced migraine attacks in migraine patients gave inconclusive results, but the study had to be terminated due to side effects, possibly from the interaction of GTN and the study drug.…”

Section: Anticonvulsantsmentioning

confidence: 99%

New drugs for migraine

2009

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After the triptans, a calcitonin gene-related peptide blocker (telcagepant) is the first acute medicine that has been developed primarily for treatment of acute migraine. Otherwise, the new drugs have been developed first for other purposes, like anticonvulsants, antihypertensives and antidepressants used for migraine prophylaxis. For acute attacks, a new way to administer a traditional drug like dihydroergotamine is under way, and documentation of efficacy in migraine has been gained for some commonly used painkillers and anti-inflammatory drugs, and for some herbal extracts. Based on insights into the basic pathophysiological mechanisms of the disorder, some drugs have been developed which seem promising in early phase II studies (NOS inhibitors and 5HT1F-receptor agonists). In the future, development and enhancements of existing medicines must be accompanied by increased efforts to develop truly new migraine drugs based on knowledge of the pathophysiology if one wishes to reduce substantially the great burden migraine poses on patients and society.

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“…Lamotrigine is used for the treatment of epilepsy, neuropathic pain, migraine, short-lasting, unilateral neuralgiform headache attacks with conjunctival injection and tearing (SUNCT) syndrome, or bipolar mood disorders [6,7]. In animal experiments, lamotrigine has been shown to exert vasodilating properties [4,8]. Whether the concomitant myopathy and malignant hyperthermia have played an additional role remains unclear.…”

Section: Discussionmentioning

confidence: 98%