mdl-100907 and Migraine-Disorders

5-HT(2) receptors mediate a large array of physiological and behavioral functions in humans via three distinct subtypes: 5-HT(2A), 5-HT(2B)and 5-HT(2C). While selective 5-HT(2A)antagonists have been known for some time, knowledge of the precise role played by the 5-HT(2B)receptor was hampered by the existence of solely 5-HT(2B)5-HT(2C) mixed antagonists. However, selective 5-HT(2B)antagonists began recently to emerge in the literature. Indeed, four structural classes belonging to the piperazine, indole, naphthylpyrimidine and tetrahydro-beta-carboline scaffolds were reported. In this paper, we will briefly review the structural and pharmacological features of selective 5-HT(2B) antagonists, including patent literature of the last five years.

Topics: Animals; Binding, Competitive; Drug Design; Humans; Irritable Bowel Syndrome; Ligands; Migraine Disorders; Molecular Structure; Serotonin 5-HT2 Receptor Antagonists; Serotonin Antagonists

Experimental and pilot clinical trials suggest the role of melatoninergic systems in the pathogenesis of migraine and the treatment effect of drugs acting on melatonin receptors. Authors studied the efficacy of the MT1- and MT2 agonist and selective 5-HT2C receptor antagonist agomelatine in the migraine prevention. Twenty patients with migraine, aged from 23 to 45 years, were treated with agomelatin in dose 25 mg per day during 3 months. The frequency of migraine attacks decreased from 7.4±2.4 to 3.8±1.4 (p=0.025), the duration and intensity of attacks decreased from 38.0±14.10 h to 24.0±6.1 h (p=0.018). The increase of treatment efficacy index, the decrease of headache impact on the general state measured with the VAS (from 8.1±1.8 to 7.2±1.6; p=0.01) and quality of life (HIT-6 index) as well as the duration of disability caused by headache (HALT index) were seen. The reduction of depression severity and normalization of night sleep were found in patients treated with agomelatin.

Topics: Acetamides; Adult; Female; Humans; Male; Middle Aged; Migraine Disorders; Receptor, Melatonin, MT1; Receptor, Melatonin, MT2; Serotonin 5-HT2 Receptor Antagonists; Treatment Outcome; Young Adult

Experiments on rats showed that meta-chlorophenylpiperazine, as well as serotonin, decreases cerebral blood flow registered in internal carotid artery of narcotized animals. Therefore, this agonist of postsynaptic 5HT(2B/2C) receptors can be used for directed search of new antimigraine drugs. Tropoxin (10 mg/kg) substantially reduces constrictor reactions of cerebral blood vessels induced by meta-chlorophenylpiperazine. The effect was observed during both prophylaxis and treatment of the model disorder with this drug.

Topics: Animals; Aza Compounds; Blood Pressure; Bridged Bicyclo Compounds, Heterocyclic; Carotid Artery, Internal; Cerebrovascular Circulation; Drug Interactions; Male; Migraine Disorders; Piperazines; Rats; Receptor, Serotonin, 5-HT2B; Receptor, Serotonin, 5-HT2C; Serotonin; Serotonin 5-HT2 Receptor Agonists; Serotonin 5-HT2 Receptor Antagonists; Vasoconstriction

Many dopamine antagonists are proven acute migraine treatments. Genetic studies also imply that polymorphisms in dopamine genes (DRD2 receptors) in persons with migraine may create dopamine hypersensitivity. However, treatment is limited by the adverse event profiles of conventional neuroleptics including extrapyramidal symptoms, anticholinergic and antihistaminergic effects, hyperprolactinemia, and prolonged cardiac QT interval. Atypical neuroleptics cause less extrapyramial symptoms and some atypical neuroleptics, including olanzapine and quetiapine, may be beneficial as both acute and preventive migraine treatment. The combination of prochlorperazine, indomethacin, and caffeine is effective in the treatment of the acute migraine attack. The mechanism of action by which neuroleptics relieve headache is probably related to dopamine D2 receptor antagonist. Other actions via serotonin (5HT) receptor antagonists may also be important, particularly for migraine prevention. Additional studies to clarify the mechanism of action of neuroleptics in migraine could lead to new drugs and better management of migraine.

Topics: Antipsychotic Agents; Benzodiazepines; Brain; Caffeine; Dibenzothiazepines; Dopamine; Dopamine Antagonists; Dopamine D2 Receptor Antagonists; Drug Interactions; Female; Humans; Hyperprolactinemia; Indomethacin; Male; Migraine Disorders; Neural Pathways; Olanzapine; Prochlorperazine; Quetiapine Fumarate; Randomized Controlled Trials as Topic; Serotonin 5-HT2 Receptor Antagonists; Serotonin Receptor Agonists; Treatment Outcome