Sumatriptan is a serotonin (5-HT1B/1D) receptor agonist indicated for acute treatment of migraine with or without aura in adults. Sumatriptan is structurally similar to serotonin (5-HT), and is a 5-HT receptor (types 5-HT1D and 5-HT1B) agonist. The specific receptor subtypes it activates are present on the cranial arteries and veins. Acting as an agonist at these receptors, sumatriptan reduces the vascular inflammation associated with migraines. The specific receptor subtype it activates is present in the cranial and basilar arteries. Activation of these receptors causes vasoconstriction of those dilated arteries. Sumatriptan is also shown to decrease the activity of the trigeminal nerve, which presumably accounts for sumatriptan's efficacy in treating cluster headaches. The injectable form of the drug has been shown to abort a cluster headache within 30 minutes in 77% of cases. Sumatriptan is effective for ending or relieving the intensity of migraine and cluster headaches. It is most effective taken early after the start of the pain. Injected sumatriptan is more effective than other formulations. Large doses of sumatriptan can cause sulfhemoglobinemia, a rare condition in which the blood changes from red to greenish-black, due to the integration of sulfur into the hemoglobin molecule. Serious cardiac events, including some that have been fatal, have occurred following the use of sumatriptan injection or tablets. Events reported have included coronary artery vasospasm, transient myocardial ischemia, myocardial infarction, ventricular tachycardia, and ventricular fibrillation (V-Fib).

The isolation and naming of ergotamine by Stoll occurred in 1925 but the complete elucidation of structure was not achieved until 1951, with synthesis following some 10 years later. Current sources of ergotamine include the isolation from field ergot and fermentation broth, as well as synthesis via coupling of (+)-lysergic acid with the appropriate synthetic peptidic moiety. Ergotamine was introduced into world commerce in 1921, and is currently marketed as its water soluble tartrate salt. Ergotamine is a partial agonist at various tryptaminergic receptors (including the serotonin receptor [5-HT2]) and at various α-adrenergic receptors in blood vessels and various smooth muscles. It is likely that the major activity of ergotamine and related alkaloids is one of agonism at the 5-HT1B/1D receptors, just as with the “triptan” antimigraine compounds. FDA-labeled indications for ergotamine tartrate are in the abortion or prevention of vascular headaches, such as migraine, migraine variant, cluster headache, and histaminic cephalalgia.

Psilocybin is a naturally occurring psychedelic prodrug compound produced by more than 200 species of mushrooms, collectively known as psilocybin mushrooms. Once ingested, psilocybin is rapidly metabolized to the psilocin, which then acts on serotonin receptors in the brain. Psilocybin was identified as the active hallucinogenic compound in magic mushrooms in 1959, but humans have used assorted psilocybin mushrooms in religious ceremonies since prehistoric times. In the 1960's psilocybin was marketed for use as a treatment for various psychoses, however, it was withdrawn from the market when the regulatory environment changed. Recently there has been as renewed interest in studying the medicinal uses of psilocybin for treatment of anxiety, depression, migraine headaches, addictions, and other neuropsychiatric conditions.

Donitriptan hydrochloride (F 11356) was developed by Pierre Fabre as a brain penetrant 5-HT1B/1D agonist. Which inhibits capsaicin-induced external carotid vasodilation and produces selective carotid vasoconstriction in various animal species. In January 2001, donitriptan had completed phase I trials for migraine and was scheduled to enter phase II development, but before development in phase II, this drug was discontinued.

Relenopride (YKP-10811) is a serotonin 4 (5-HT4) receptor agonist that was developed for regulation of gastric motility. It improved antral contractions and accelerated gastric emptying in dogs and had no adverse effects. Phase II clinical trials have investigated the efficacy and safety of relenopride in patients with (chronic and functional) constipation and irritable bowel syndrome (IBD). Relenopride was reported to accelerate gastrointestinal motility and colonic transit and improve bowel functions in patients with functional constipation, compared with placebo.

Sunepitron (CP-93,393) is an anxiolytic drug with highly selective serotonin 5-hydroxytryptamine 1A autoreceptor agonist, alpha2-adrenergic antagonist, and dopamine D2 agonist properties. Sunepitron hydrochloride had been in Phase III clinical trials by Pfizer for the treatment of anxiety disorder and depression. However, this research has been discontinued.

Indorenate (TR3369, INDO) is a serotonin-like compound with high affinity for 5- HT1A receptors and a lower affinity for 5-HT1C and 5-HT1B receptors. Indorenate possesses antihypertensive and anxiolytic activity in animal behaviour tests. Similar to other serotonin receptor agonists, Indorenate also has anorectic activity; this effect was blocked by the administration of the 5-HT2A/2C receptor antagonists cinanserin, cyproheptadine, metergoline and methysergide. A unpublished clinical trial confirmed its antihypertensive activity in men.

IPSAPIRONE, an azapirone derivative structurally unrelated to the benzodiazepines, is a selective 5-HT1A serotonin receptor agonist. It has antidepressant and anxiolytic effects. IPSAPIRONE was studied in several clinical trials for depression and generalized anxiety disorder.

Quizapine is a piperazine-based nonselective serotonin (5-HT) receptor agonist with antidepressant and oxytocic activities. Quipazine targets and binds to serotonin receptors, particularly to the 5HT2A and 5HT3 receptors. Quipazine is a potential anti-parkinsonian agent. Serotonin receptor activation by quipazine may lead to smooth muscle contraction and antidepressant effects. quipazine, a central serotonergic agent, counteracted some of the drug-induced symptoms of pseudoparkinsonism in laboratory animals. Cholinergic, dopaminergic and histaminergic receptors play an important role in the manifestations of these symptoms.

Vabicaserin is a 5-hydroxytryptamine 2C (5-HT2C) receptor-selective agonist with an EC50 of 8 nM. Pfizer was developing vabicaserin, an oral serotonin (5-HT)2C receptor agonist, for the treatment of schizophrenia and bipolar disorder. Vabicaserin decreases nucleus accumbens extracellular dopamine levels in rats, without affecting striatal dopamine, indicating mesolimbic selectivity. Vabicaserin had been in phase II clinical trials for the treatment of schizophrenia. However, research of Vabicaserin for the treatment schizophrenia and obesity was discontinued.