Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “Sumatriptan”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 1,729 records · Page 96Linked to original sources
PubMed1993

Orofacial neuralgia. Diagnosis and treatment guidelines.

Patients with facial pain, without overt dental disease, are often seen in both medical and dental practice. The differential diagnosis includes (a) cluster headache, in which patients have severe unilateral pains lasting 30 to 120 minutes that respond to verapamil, corticosteroids or lithium; (b) migraine, in which attacks are longer and are often accompanied by nausea and visual disturbance, and can be managed using anti-inflammatory analgesics, with or without metoclopramide, or sumatriptan, although frequent attacks are best suppressed by continuous propranolol or pizotifen; (c) trigeminal neuralgia, knifelike unilateral pains usually responsive to carbamazepine; and (d) temporal arteritis, a steadier pain very responsive to corticosteroids. There is no evidence that continuous 'idiopathic facial pain' is a result of malocclusion (i.e. the way in which the teeth fit together), and its aetiology remains obscure, although there is some biochemical evidence linking it to depression. Many patients respond to simple analgesia and firm reassurance from the physician, although antidepressant therapy (e.g. nortriptyline or dothiepin) is often of great value.

Anti-Inflammatory Agents↗
PubMed2001

Irritable bowel syndrome: new agents targeting serotonin receptor subtypes.

Although the past few years have seen an exponential growth of compounds of potential interest for the treatment of functional gastrointestinal (GI) tract disorders, the gap that still exists between basic and clinical research is easily noticed if one considers the relative paucity of drugs that have received marketing authorisation for the treatment of irritable bowel syndrome (IBS). Traditional efficacy outcomes in drug development for IBS include the ability of the compound to affect GI tract motility (i.e. to exert a prokinetic or an antispasmodic effect), which is thought to be of importance if a motor disorder is the underlying pathophysiological mechanism. More recently, altered visceral sensitivity to a distending stimulus has been suggested to be a key pathophysiological feature, at least in some patients, and has become a target for therapeutic interventions. However, there is now growing consensus that the primary outcome measure in the treatment of functional disorders are those that reflect overall control of the patient's symptoms (pain, diarrhoea, constipation) in everyday situations such as the clinical global improvement scales. Although, in general, guidelines on the design of treatment trials for functional GI tract disorders advise against subcategorisation of patients according to the main symptom (because of symptom instability), subcategorisation indeed makes sense especially in IBS (constipation- or diarrhoea-predominant). Compounds with a specific indication for each subpopulation of patients are now emerging. The rationale for investigations on serotonin (5-hydroxytryptamine; 5-HT) receptor ligands in IBS rests mainly on the fact that serotonin, which may be released by enterochromaffin-like cells in the GI tract as well as from other sources, has a number of well documented motor effects on the GI tract and can produce hyperalgesia in several experimental models. Serotonin receptors belonging to the 5-HT3 and 5-HT4 subtype are the most extensively studied in gastroenterology, although hitherto 'orphan' receptor subtypes, such as the 5-HT7 and the 5-HT(1B/D) receptors, are now emerging. Among 5-HT3 receptor antagonists, alosetron was recently approved for the treatment of diarrhoea-predominant IBS and is an example of a compound that, at least theoretically, may act at multiple levels: by inhibiting visceral sensitivity, by increasing compliance, and by inhibiting excitatory 5-HT3 receptors located on both ascending and descending neuronal pathways involved in peristalsis. For this reason, 5-HT3 receptor antagonists may slow transit, hence the specific indication of alosetron in diarrhoea-predominant IBS. However, alosetron has been recently withdrawn by the manufacturer because of safety concerns. Hypomotility remains an attractive therapeutic target in IBS and the new generation of prokinetics includes several partial agonists at the 5-HT4 receptor, such as tegaserod (HTF-919) and prucalopride (R0-93877). In addition, preliminary evidence suggests that 5-HT4 receptors may also be involved in the modulation of visceral sensitivity. Second-generation 5-HT4 receptor agonists seem to be devoid of the QT-prolonging effects observed in some clinical circumstances with cisapride and may be more active at the colonic level. Piboserod (SB-207266A) is a 5-HT4 receptor antagonist under development for the treatment of diarrhoea-predominant IBS. Finally, interest in 5-HT7 and 5-HT(1B/D) receptor subtypes stems from the observation that the former receptors mediate smooth muscle relaxation (at least in the human colon), whereas sumatriptan (a 5-HT(1B/D) receptor agonist) can affect GI tract motility and visceral sensitivity.

Clinical Trials as Topic↗
PubMed2002

Cluster headache: aetiology, diagnosis and management.

Cluster headache is characterised by repeated attacks of strictly unilateral pain in the orbital region associated with local autonomic symptoms or signs. The attacks are brief but of a very severe, almost excruciating intensity. For unknown reasons males are affected more often than females. Recent studies suggest that an autosomal dominant gene has a role in some families with cluster headache. Hormonal studies indicate a dysfunction in the central nervous system. Neuroimaging has revealed primary defects in the hypothalamic grey matter. Local homolateral dilatation in the intracranial segment of the internal carotid and ophthalmic arteries during attacks is the result of a generic neurovascular activation, probably mediated by trigeminal parasympathetic reflexes. Sumatriptan 6mg subcutaneously is the drug of choice in the treatment of acute attacks. Inhalation of 100% oxygen can also be recommended. In the prophylactic treatment, verapamil is the first option. Other drugs that can be considered are corticosteroids, which may induce a remission of frequent, severe attacks, and lithium. Oral ergotamine tartrate may be sufficient for patients with night attacks and/or short, rather mild to moderately severe cluster headache periods. Third line drugs are serotonin inhibitors (methysergide and pizotifen) and valproic acid. Patients should be encouraged to keep headache diaries and be carefully instructed about the nature and treatment of the headaches. Alcohol can bring on extra attacks and should not be consumed during active periods of cluster headache.

Cluster Headache↗
PubMed1997

The impact of drug therapy on quality of life in headache and migraine.

Although headache is among the most common and costly disorders in primary care, our understanding of its direct impact on the quality of life of affected individuals is incomplete. While studies evaluating the role of headache on health-related quality of life and healthcare economics are starting to appear in the medical literature, the effect of pharmacotherapy in improving quality of life is only beginning to be studied. At present, studies evaluating health-related quality of life in patients with migraine who are undergoing treatment are limited to 3 agents: sumatriptan, flurbiprofen and diclofenac. Several studies have consistently indicated that these drugs benefit patients by improving key dimensions of health-related quality of life or patients' sense of well-being to a significant extent. Given the magnitude of functional and emotional impairment associated with chronic headache disorders, assessing patients' perceptions of their quality of life makes a useful contribution to the evaluation of therapeutic interventions and should supplement traditional clinical endpoints in determining the effectiveness of new drugs.

Headache↗
PubMed2005

An economic evaluation of rizatriptan in the treatment of migraine.

BACKGROUND: Migraine is a common, chronic, neurovascular disorder, generally characterised by attacks of severe headache and autonomic nervous system dysfunction. Triptans are selective serotonin 5-HT(1B/1D) receptor agonists that represent effective therapeutic options for moderate-to-severe migraine attacks but with higher acquisition costs relative to usual care therapies. OBJECTIVE: The objective of this study was to examine the cost effectiveness of rizatriptan treatment compared with 'Usual Care' or other triptans available in Canada for patients with moderate-to-severe migraine for whom other therapies (e.g. NSAIDs, simple analgesics) are insufficient or contraindicated. METHODS: A decision-analysis model was created to estimate migraine treatment costs over a 24-hour period in patients with a diagnosis of moderate-to-severe migraine as defined by the International Headache Society criteria. Costs and clinical outcomes were observed over a 24-hour period from therapy initiation. Efficacy measures consisted of 'pain-free response at 2 hours' and 'sustained pain free for 2-24 hours'. Oral rizatriptan 10 mg was compared with other oral triptans (i.e. sumatriptan 50 or 100 mg), naratriptan 2.5 mg and zolmitriptan 2.5 mg, based on a meta-analysis and compared with 'Usual Care' based on a naturalistic study of people who experience migraine and who were similar to the target population. 'Usual Care' was defined as an aggregate of medications prescribed for the Canadian population for the indication of migraine, weighted by the relative frequency of use of prescriptions over a 1-year period. Analyses were conducted from the Ontario (Canada) Ministry of Health and Long-Term Care (MOH<C) perspective and the broader societal perspective. Results are presented as the cost per migraine attack aborted (i.e. pain free at 2 hours), as well as the cost per QALY. Several one-way sensitivity analyses were conducted to test the robustness of the model. All costs are expressed in 2002 $Can. RESULTS: Cost estimates are similar to previously published Canadian studies. Rizatriptan compared with 'Usual Care' produced an incremental cost per attack aborted of $Can49.82 and a cost per QALY gained of $Can31 845 from the MOH<C perspective. When a societal perspective was considered (which included time loss from paid and unpaid work activities), rizatriptan dominates 'Usual Care': that is, it is cost saving and more effective. All other triptans are also dominated by rizatriptan as they offer higher costs and lower efficacy. CONCLUSIONS: This study shows that rizatriptan treatment for patients who experience moderate-to-severe migraines may represent a cost-effective strategy for improving care of migraine patients in Canada.

Canada↗
PubMedDate not supplied

Drug treatment of migraine in children: a comparative review.

Migraine according to the criteria of the International Headache Society, occurs in about 3 to 7% of all children. Despite this high incidence, and unlike the situation with adult migraine, only a very few controlled trials have investigated the acute and prophylactic treatment of migraine in children. In the acute migraine attack, ibuprofen 10 mg/kg and paracetamol (acetaminophen) 15 mg/kg have been shown to be effective, with only a few adverse effects. In severe migraine attacks, dihydroergotamine mesylate (dihydroergotamine) administered orally (20 to 40 microg/kg) or intravenously (maximum 1 mg/day) may be helpful, but there have been no large placebo-controlled trials of this treatment. Oral sumatriptan has not been effective in several double-blind and placebo-controlled trials; administered subcutaneously, this drug might be helpful but the only data for this application come from open trials. For migraine prophylaxis, only flunarizine 5 mg/day has been shown to be effective in more than 1 double-blind, placebo-controlled trial. Some evidence also exists that propranolol >60 mg/day and pizotifen 0.5 to 1.5 mg/day are effective; however, the results from different trials are contradictory. For all other drugs studied in migraine prophylaxis, the results remain vague (e.g. amitriptyline, nimodipine, trazodone) or suggest inefficacy (e.g. timolol, clonidine, tryptophan). In migraine-related disorders, pizotifen 0.5 to 0.75 mg/day for abdominal migraine and flunarizine 10 to 25 mg/day for alternating hemiplegia have been shown to be effective. Most of the drugs used in the treatment of migraine in children are well tolerated and without relevant adverse effects. In migraine prophylaxis, the most common adverse effects are drowsiness and bodyweight gain.

Child↗
PubMed2002

Abdominal migraine: evidence for existence and treatment options.

There is evidence to suggest that, in children, episodic abdominal pain occurring in the absence of headache may be a migrainous phenomenon. There are four separate strands of evidence for this: the common co-existence of abdominal pain and migraine headaches; the similarity between children with episodic abdominal pain and children with migraine headaches, with respect to social and demographic factors, precipitating and relieving factors, and accompanying gastrointestinal, neurological and vasomotor features; the effectiveness of nonanalgesic migraine therapy (such as pizotifen, propanolol, cyproheptadine and the triptans) in abdominal migraine; and the finding of similar neurophysiological features in both migraine headache and abdominal migraine. Abdominal migraine is rare, but not unknown, in adults. Many families are content with a diagnosis and reassurance that the episodes, though distressing, are not the result of serious pathology. Some patients respond to simple dietary and other prophylactic measures. There is scant evidence on which to base recommendations for the drug management of abdominal migraine. What little literature exists suggests that the antimigraine drugs pizotifen, propanolol and cyproheptadine are effective prophylactics. Nasal sumatriptan (although not licensed for pediatric use) may be effective in relieving abdominal migraine attacks.

Abdominal Pain↗
PubMed2004

Human vaginal mucosa as a model of buccal mucosa for in vitro permeability studies: an overview.

The buccal cavity is attractive for noninvasive, controlled transmucosal delivery of both local and systemic therapeutically active compounds. Administering drugs via this route is advantageous due to the rich vasculature of the oral mucosa, and the absence of gastrointestinal and "first-pass" hepatic degradation. Moreover, the barrier properties of the oral mucosa against noxious substances and its role in disease require further investigation. However, the scarcity of sizeable specimens of human oral mucosa for in vitro experimental studies has hampered research on this tissue. For this reason we developed a model in which human vaginal mucosa is used as a substitute for buccal mucosa. In this article the quality and predictive value of the human vaginal/buccal in vitro model with respect to a number of drugs and other chemical compounds differing widely in molecular size and lipophilicity, including water, arecoline, arecaidine, benzo[a]pyrene, 17beta-estradiol, sumatriptan, vasopressin and dextrans, are reviewed. In addition some applications of the model for investigating the effect of areca nut extract on epithelial barrier properties, temperature effects on water and 17beta-estradiol flux rates, and cyclosporin diffusion through mucosal membranes are described. The permeability characteristics of vaginal mucosa, as a model of buccal mucosa, are compared with those of other human tissue, including mucosae from the small intestine and colon.

Female↗
PubMed2002

Recent advances in 5-HT1B/1D receptor antagonists and agonists and their potential therapeutic applications.

The human 5-HT(1B) and 5-HT(1D) receptors are especially similar in sequence despite being encoded by two distinct genes. Although, human 5-HT(1B) and 5-HT(1D) receptors have been pharmacologically differentiated using nonselective 5-HT(1B/D) receptor antagonists such as ketanserin (1), ritanserin (2) and methiothepin (3), the precise function of these receptors remains undefined, and progress toward this has been hampered by the lack of selective ligands. The interest of the major pharmaceutical companies in 5-HT(1B/1D) antagonists increased by the discovery of potent and selective tools, combined with the fact that the blockade of terminal 5-HT(1B) receptors by selective antagonists has been proposed as a new approach for more efficient and/or fast-acting antidepressant drugs, since the acute blockade of these 5-HT autoreceptors will, in theory, immediately mimic their desensitization. Furthermore, it has been also suggested that supersensitive 5-HT(1B/1D) receptors may be involved in the pathophysiology of obsessive compulsive disorders (OCD). In the 5-HT(1B/1D) agonist field, since the discovery of sumatriptan (26) (a 5-HT(1B/1D) receptor agonist) as an effective treatment for migraine headache, intensive research in this area has led to several second-generation compounds, a few of which have either entered the market place or are in late clinical trials. Beside the antimigraine activity of the 5-HT(1B/1D) agonists in clinical evaluation or already on the market, other potential therapeutic evaluations (such as gastric motor effect, bipolar disorder, autism, anti-aggressive effects) with these drugs are being investigated. This article highlights and reviews the research advances published in the 5-HT(1B/1D) antagonist and agonist literature. The article is supplemented with selected references on the design, synthesis and development of novel 5-HT(1B/1D) agents, and on studies to understand their mechanism and pathophysiology. Emphasis is given to recent advances in the potential therapeutic applications of 5-HT(1B/1D) serotonergic agents. By no means has any attempt been made to exhaustively review the literature but rather, primary references along with citations to recent literature reviews have been included in each section.

Animals↗
PubMed1993

Structure functional expression and spatial distribution of a cloned cDNA encoding a rat 5-HT1D-like receptor.

Using polymerase chain reaction (PCR) a complementary DNA (cDNA) encoding a 5-hydroxytryptamine (5-HT) receptor was isolated from rat forebrain. The amplified cDNA specifies an open reading frame of 374 amino acids comprising seven putative transmembrane regions. Expression of the cloned cDNA in human embryonic kidney cells (HEK 293) was used to establish the pharmacological profile of the encoded receptor polypeptide. Membranes containing the cloned receptor showed high affinity binding of [3H]-5-HT. Competition binding experiments with a variety of serotonin receptor ligands displayed a rank order of affinities corresponding to a 5-HT1D subtype: 5-CT > 5-HT = metergoline > CGS 12066 > methysergide > sumatriptan > mianserin = (-)alpha-Me-5-HT = yohimbine > 8-OH-DPAT > or = rauwolscine > spiperone > DOI > propranolol > or = 2-Me-5-HT > or = ICS 205930. Ketanserin and ritanserin displaced [3H]-5-HT-binding in a biphasic manner. In situ hybridization revealed highest expression of the corresponding mRNA in the pyramidal layer of the olfactory tubercle and the nucleus caudatus and accumbens.

Amino Acid Sequence↗
PubMed2000

Obsessive compulsive disorder: serotonin and beyond.

OCD was considered a rare, treatment refractory disorder of psychological origin, up until 20 years ago. Research in the last two decades has altered the perspectives regarding OCD. It is now clear that OCD is a prevalent disorder--about 2% of the population suffer from OCD--and that it is amenable both to psychological (cognitive-behavioural approach) and pharmacological intervention (with serotonergic medication). The biochemical and neuroanatomical (the frontal basal-thalamo cortical circuit) pathophysiology of OCD is also beginning to emerge. OCD is unique with regards to its specific response to serotonergic medication that blocks reuptake. Clomiprimine, fluoxetine, fluvoxemine, paroxetine, sertraline and citalopram were all found to be effective treatments for OCD based on large, multicentre, double-blind, placebo-controlled studies. As only serotonergic medications appear to be effective in OCD, the serotonergic hypothesis has been formulated and tested. Indeed, pharmacological challenges with specific serotonin agonists such as mCPP and sumatriptan, which were associated with transient exacerbation of OCD symptoms, are in line with the specific role of 5HT in the pathogenesis of OCD. However, this serotonergic hypothesis, while necessary, is not sufficient. It is clear that the dopaminergic and autoimmune mechanism are also implicated in the pathogenesis of OCD. Further studies are required to understand the relevance of the serotonergic and non-serotonergic systems in OCD, and to highlight the various possible subtypes of this intriguing disorder.

Dopamine↗
PubMed1997

Menstrual migraine. Methods of prevention and control.

In many women, migraine headaches are clearly linked to estrogen levels: the incidence rises at the menarche; attacks may be precipitated by falling estrogen levels before menses; and symptoms usually improve during pregnancy when there are noncyclic high levels of estrogen. Decreased estrogen production in the perimenopausal phase may trigger an exacerbation of migraine. However, after menopause when estrogen levels are noncyclic and low, there may be an improvement in migraine. The falling estradiol level rather than the absolute level provides the trigger for menstruation-associated migraine. Treatment involves both prophylactic and acute measures. Therapy for an acute attack is similar to that for nonmenstrual migraine. Sumatriptan is equally effective for both nonmenstrual and menstrual migraine.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed1997

Headaches in children. When is a complete diagnostic workup indicated?

Migraines, migraine variants, and other headache types often present for the first time during childhood; they require follow-up and, when appropriate, further investigation. Management of migraine should include a discussion of therapeutic goals with patients and parents. Appropriate medications are limited in younger children, but older children and adolescents have more options, such as the new serotonin-agonist agents (eg, sumatriptan succinate), which are now undergoing study for use in this age-group. Preventive therapy, both nonpharmacologic and pharmacologic, should be described to patients and parents so they understand the options available if headaches recur.

Child↗
PubMed1999

Treatment of migraine headaches.

Migraine headaches are common and costly. Patients with migraine frequently seek medical attention from primary care physicians. Although effective therapy is available, migraine is underdiagnosed and undertreated. The 3 main forms of management are avoidance of migraine triggers, treatment of the acute attack with medications, and regular use of preventive medications. Although changes in lifestyle can help to prevent some migraine attacks, the mainstay of treatment is the use of medications taken early during the attack. A wide variety of single-ingredient and combination over-the-counter and prescription medications are now available. Especially effective are the new selective serotonin (5-hydroxytryptamine1 receptor) agonists such as sumatriptan. For patients who have frequent and severe migraine headaches despite the use of acute treatment, preventive medications, including beta-adrenergic blockers, calcium channel blockers, tricyclic antidepressants, and one anticonvulsant, should be considered. The vast majority of patients with migraine can be helped.

Acute Disease↗
PubMed1998

Nitric oxide is produced via 5-HT1B and 5-HT2B receptor activation in human coronary artery endothelial cells.

The aim of this study is to clarify the serotonin (5-HT) receptor subtypes responsible for 5-HT-induced nitric oxide (NO) production in cultured human coronary artery endothelial cells (HCAECs). Reverse transcription-polymerase chain reactions revealed that HCAECs possessed only 5-HT1B and 5-HT2B receptor mRNAs. 5-HT (0.001-10 mumol/L) induced nitrite production from HCAEC. A selective 5-HT1B/1D agonist sumatriptan (0.01-10 mumol/L) caused nitrite production. A selective 5-HT2 agonist (+/-)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane hydrochloride (DOI, 0.01-10 mumol/L) also mimicked the effect of 5-HT. The 5-HT-induced nitrite production was completely inhibited by the nonselective 5-HT1/2 antagonist methiothepin (0.1 mumol/L), but not by the 5-HT2A/2C antagonist ketanserin (0.1 mumol/L). Each of these agonists evoked the elevation of intracellular Ca2+ concentration in HCAECs. These findings suggest that 5-HT-induced NO production is mediated by both of 5-HT1B and 5-HT2B receptor activation in HCAECs. Thus, the 5-HT-evoked endothelium-dependent relaxation of human coronary arteries in vivo might be evoked by net effects of the activation of these receptor subtypes.

Calcium↗
PubMed1999

Modified ligand binding to the naturally occurring Cys-124 variant of the human serotonin 5-HT1B receptor.

A substitution of phenylalanine by cysteine in position 124 is the only known naturally occurring variant of the human 5-HT1B (h5-HT1B) receptor. The present study was designed to evaluate the potential influence of the Cys-124 variant on pharmacological properties of the receptor and to test for an involvement of the mutation in the genetic predisposition to schizophrenia or bipolar affective disorder. Binding of [3H]5-carboxamidotryptamine ([3H]5-CT) and its competition with serotonin receptor agonists and antagonists were determined in COS-7 cells transfected with the wild-type or the variant h5-HT1B receptor cDNA. In saturation experiments with [3H]5-CT, the maximum binding (Bmax) of the variant receptor was approximately 30% of the wild-type receptor. In competition experiments with 1 nM [3H]5-CT, the following serotonin receptor ligands exhibited a two to three times higher affinity for the mutant than for the wild-type receptor: dihydroergotamine, L-694,247, SB-216641, 5-CT, 5-HT, sumatriptan, RU24969 and methysergide (compounds listed at decreasing order of potency at the wild-type receptor). In contrast, the serotonin receptor antagonist ketanserin exhibited higher binding affinity for the wild-type than for the mutant h5-HT1B receptor and GR127939, (-)propranolol and BRL-15572 showed equal affinity for both types of receptor. Mutation screening of schizophrenic and bipolar patients revealed no relationship between the variant receptor and development of disease. In conclusion, our data suggest that the Cys-124 variant significantly affects the pharmacological properties of the h5-HT1B receptor. Carriers of the variant may exhibit differences in response to drugs acting on the h5-HT1B receptor or may develop side-effects to such agents.

Animals↗
PubMed1999

[Chronic recurrent headache without neurological abnormalities. Practice guidelines of the Netherlands Society of Neurology].

The diagnosis of chronic recurrent headache without neurological abnormalities is based on the anamnesis and physical examination; EEG or other supplementary examinations as a rule are not indicated. Regarding treatment of migraine, a distinction is made between attack treatment, preferably with non-specific drugs (analgetics and non-steroid anti-inflammatory agents (NSAIDs)) after aural symptoms if any, and prophylactic treatment (agents of choice: beta-receptor blockers). Cluster headache requires adequate treatment as soon as possible after the diagnosis, usually with attack treatment (sumatriptan s.c. or oxygen) as well as prophylactic treatment (agent of choice: verapamil). In the treatment of tension headache, a non-pharmaceutical treatment (relaxation) is to be preferred to pharmacotherapy (tricyclic antidepressants). Patients with chronic recurrent headache should be asked about excessive use of analgetics and caffeine-containing beverages, because these (or abstinence from them) may be the cause of the symptoms.

Chronic Disease↗
PubMed1999

F 11356, a novel 5-hydroxytryptamine (5-HT) derivative with potent, selective, and unique high intrinsic activity at 5-HT1B/1D receptors in models relevant to migraine.

F 11356 (4-[4-[2-(2-aminoethyl)-1H-indol-5-yloxyl]acetyl]piperazinyl-1-yl] ben zonitrile) was designed to take advantage of the superior potency and efficacy characteristics of 5-hydroxytryptamine (5-HT) compared with tryptamine at 5-HT1B/1D receptors. F 11356 has subnanomolar affinity for cloned human and nonhuman 5-HT1B and 5-HT1D receptors, and its affinity for 5-HT1A and other 5-HT receptors, including the 5-ht1F subtype, is 50-fold lower and micromolar, respectively. In C6 cells expressing human 5-HT1B or human 5-HT1D receptors, F 11356 was the most potent compound in inhibiting forskolin-induced cyclic AMP formation (pD2 = 8.9 and 9.6), and in contrast to tryptamine and derivatives, it produced maximal enhancement of [35S]guanosine-5'-O-(3-thio)triphosphate-specific binding equivalent to 5-HT. F 11356 was equipotent to 5-HT (pD2 = 7.1 versus 7.2) and more potent than tryptamine derivatives in contracting rabbit isolated saphenous vein. In isolated guinea pig trigeminal ganglion neurons, F 11356 was more potent (pD2 = 7.3 versus 6.7) and induced greater increases in outward hyperpolarizing Ca2+-dependent K+ current than sumatriptan. In anesthetized pigs, F 11356 elicited highly cranioselective, more potent (from 0.16 microgram/kg i.v.) and greater carotid vasoconstriction than tryptamine derivatives. Decreases in carotid blood flow were observed in conscious dogs from 0.63 mg/kg oral F 11356 in the absence of changes in heart rate or behavior. Oral activity was confirmed when hypothermic responses were elicited in guinea pigs (ED50 = 1.6 mg/kg), suggesting that F 11356 also accesses the brain. F 11356 thus is a selective, high-potency agonist at 5-HT1B/1D receptors, which distinguishes itself from tryptamine and derivatives in exerting high intrinsic activity at these receptors in vascular and neuronal models relevant to migraine.

Animals↗