The Potential Anti-Migraine Compound SB-220453 does not Contract Human Isolated Blood Vessels or Myocardium; A Comparison with Sumatriptan

VanDenBrink, Antoinette Maassen; Broek, R. van den; Vries, René de; Upton, Neil; Parsons, AA; Pr, Saxena

doi:10.1046/j.1468-2982.2000.00078.x

Cited by 34 publications

(19 citation statements)

References 31 publications

(39 reference statements)

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“…In a further work using the same anaesthetized cat model, tonabersat produces a marked dose-dependent inhibition of repetitive CSD and reduces CSD-induced repetitive episodes of pial artery vasodilatation (Smith et al, 2000). When compared with the serotoninergic agonist sumatriptan (5-HT 1D,1B agonist), tonabersat seemed to be devoid of adverse cardiovascular side-effects in isolated human tissues (MaassenVanDenBrink et al, 2000). In a study using repetitive diffusion-weighted MR imaging, the inhibitory effects of tonabersat on CSD event number and duration of activity was confirmed in vivo in the cat cerebral cortex.…”

Section: Gap Junction Channels As Therapeutic Targetsmentioning

confidence: 99%

Involvement of gap junction channels in the pathophysiology of migraine with aura

Sarrouilhe¹,

Dejean²,

Mesnil³

2014

Front. Physiol.

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Migraine is a common, recurrent, and disabling primary headache disorder with a genetic component which affects up to 20% of the population. One third of all patients with migraine experiences aura, a focal neurological disturbance that manifests itself as visual, sensitive or motor symptoms preceding the headache. In the pathophysiology of migraine with aura, activation of the trigeminovascular system from the meningeal vessels mediates migraine pain via the brainstem and projections ascend to the thalamus and cortex. Cortical spreading depression (CSD) was proposed to trigger migraine aura and to activate perivascular trigeminal nerves in the cortex. Quinine, quinidine and the derivative mefloquine are able to inhibit CSD suggesting an involvement of neuronal connexin36 channels in CSD propagation. More recently, CSD was shown to induce headache by activating the trigeminovascular system through the opening of stressed neuronal Pannexin1 channels. A novel benzopyran compound, tonabersat, was selected for clinical trial on the basis of its inhibitory activity on CSD and neurogenic inflammation in animal models of migraine. Interestingly, in the time course of animal model trials, tonabersat was shown to inhibit trigeminal ganglion (TGG) neuronal-glial cell gap junctions, suggesting that this compound could prevent peripheral sensitization within the ganglion. Three clinical trials aimed at investigating the effectiveness of tonabersat as a preventive drug were negative, and conflicting results were obtained in other trials concerning its ability to relieve attacks. In contrast, in another clinical trial, tonabersat showed a preventive effect on attacks of migraine with aura but had no efficacy on non-aura attacks. Gap junction channels seem to be involved in several ways in the pathophysiology of migraine with aura and emerge as a new promising putative target in treatment of this disorder.

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Section: Gap Junction Channels As Therapeutic Targetsmentioning

confidence: 99%

Involvement of gap junction channels in the pathophysiology of migraine with aura

Sarrouilhe¹,

Dejean²,

Mesnil³

2014

Front. Physiol.

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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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“…In vitro studies using isolated coronary arteries have shown that 5-HT receptor agonists produce similar activate peripheral 5-HT 1D -receptors located on trigeminal nerve terminals surrounding blood vessels within the effects in endothelium-denuded arterial segments obtained from diseased hearts [15] and in endothelium intact dura mater [11]. The EC 50 at recombinant human 5-HT 1D -receptors is approximately 8 nm for both drugs segments obtained from donor (normal) hearts [19]. However, it is possible that the in vivo situation may be [23]).…”

Section: Analysis Of Data Preparation Of Arterial Segmentsmentioning

confidence: 99%

Comparison of the vasoconstrictor effects of the selective 5‐HT_1D‐receptor agonist L‐775,606 with the mixed 5‐HT_1B/_1D‐receptor agonist sumatriptan and 5‐HT in human isolated coronary artery

Longmore

Maguire

MacLeod

et al. 2000

Brit J Clinical Pharma

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Aims Vasoconstriction in human coronary artery can be mediated via activation of both 5-HT 2 and 5-HT 1B -receptors. Coronary vasoconstriction is a rare, but potential adverse effect of the antimigraine drug sumatriptan. In order to investigate the receptor population involved we compared the vasoconstrictor effects of sumatriptan (a mixed 5-HT 1B/1D -receptor agonist) with those of L-775,606 (a selective 5-HT 1D -receptor agonist) and 5-HT (the endogenous ligand) in human isolated coronary arteries. Methods Coronary arteries were obtained from human hearts removed prior to transplant surgery. Several endothelium denuded ring segments (4 mm in length) were obtained from each artery and mounted for isometric tension recording. Each segment was first exposed to 45 mm KCl and then to 5-HT (1 nm-100 mm). Concentration-effect curves to L-775,606 (1-(3-(5-(1,2,4-triazol-4-yl)-1H-indol-3-yl)propyl)-4-(2-(3-fluorophenyl)ethyl)piperazine) and sumatriptan were then performed in a consecutive and random manner. The response to repeated application of 5-HT was obtained in separate segments. Results Twenty-five segments from seven different coronary arteries were studied. Concentration-effect curves were fitted to the data using nonlinear regression analysis. The maximum contraction for L-775,606 was significantly less than that for sumatriptan with E max values (% relative to 45 mm KCl=100%) of 30.1±4.22 and 41.5±2.7, respectively. L-775,606 was significantly (30-fold) less potent than sumatriptan in causing contraction compared with sumatriptan (EC 50 values were 6.0 mm and 0.2 mm, respectively). For comparison the E max value for 5-HT was 77.2% and the EC 50 value was 0.2 mm. Conclusions The selective 5-HT 1D -receptor agonist L-775,606 has less propensity towards vasoconstriction in human isolated coronary artery (endothelium-denuded) than was mixed 5-HT 1B/1D -receptor agonist sumatriptan. The contractions produced were at concentrations where L-775,606 would be expected to occupy 5-HT 1B -receptors.

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The Potential Anti-Migraine Compound SB-220453 does not Contract Human Isolated Blood Vessels or Myocardium; A Comparison with Sumatriptan

Cited by 34 publications

References 31 publications

Involvement of gap junction channels in the pathophysiology of migraine with aura

Involvement of gap junction channels in the pathophysiology of migraine with aura

New drugs for migraine

Comparison of the vasoconstrictor effects of the selective 5‐HT_1D‐receptor agonist L‐775,606 with the mixed 5‐HT_1B/_1D‐receptor agonist sumatriptan and 5‐HT in human isolated coronary artery

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The Potential Anti-Migraine Compound SB-220453 does not Contract Human Isolated Blood Vessels or Myocardium; A Comparison with Sumatriptan

Cited by 34 publications

References 31 publications

Involvement of gap junction channels in the pathophysiology of migraine with aura

Involvement of gap junction channels in the pathophysiology of migraine with aura

New drugs for migraine

Comparison of the vasoconstrictor effects of the selective 5‐HT1D‐receptor agonist L‐775,606 with the mixed 5‐HT1B/1D‐receptor agonist sumatriptan and 5‐HT in human isolated coronary artery

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Comparison of the vasoconstrictor effects of the selective 5‐HT_1D‐receptor agonist L‐775,606 with the mixed 5‐HT_1B/_1D‐receptor agonist sumatriptan and 5‐HT in human isolated coronary artery