Triptans are a family of tryptamine-based drugs used as abortive medication in the treatment of migraines and cluster headaches. This drug class was first commercially introduced in the 1990s. While effective at treating individual headaches, they do not provide preventive treatment and are not considered a cure. They are not effective for the treatment of tension–type headache, except in persons who also experience migraines. Triptans do not relieve other kinds of pain.
Methysergide, sold under the brand names Deseril and Sansert, is a monoaminergic medication of the ergoline and lysergamide groups which is used in the prophylaxis and treatment of migraine and cluster headaches. It has been withdrawn from the market in the United States and Canada due to adverse effects. It is taken by mouth.
Dihydrexidine (DAR-0100) is a moderately selective full agonist at the dopamine D1 and D5 receptors. It has approximately 10-fold selectivity for D1 and D5 over the D2 receptor. Although dihydrexidine has some affinity for the D2 receptor, it has functionally selective (highly biased) D2 signaling, thereby explaining why it lacks D2 agonist behavioral qualities.
A serotonin receptor agonist is an agonist of one or more serotonin receptors. They activate serotonin receptors in a manner similar to that of serotonin, a neurotransmitter and hormone and the endogenous ligand of the serotonin receptors.
The nociceptin opioid peptide receptor (NOP), also known as the nociceptin/orphanin FQ (N/OFQ) receptor or kappa-type 3 opioid receptor, is a protein that in humans is encoded by the OPRL1 gene. The nociceptin receptor is a member of the opioid subfamily of G protein-coupled receptors whose natural ligand is the 17 amino acid neuropeptide known as nociceptin (N/OFQ). This receptor is involved in the regulation of numerous brain activities, particularly instinctive and emotional behaviors. Antagonists targeting NOP are under investigation for their role as treatments for depression and Parkinson's disease, whereas NOP agonists have been shown to act as powerful, non-addictive painkillers in non-human primates.
The orexin receptor (also referred to as the hypocretin receptor) is a G-protein-coupled receptor that binds the neuropeptide orexin. There are two variants, OX1 and OX2, each encoded by a different gene (HCRTR1, HCRTR2).
Mesulergine (INN) (developmental code name CU-32085) is a drug of the ergoline group which was never marketed. It acts on serotonin and dopamine receptors. Specifically, it is an agonist of dopamine D2-like receptors and serotonin 5-HT6 receptors and an antagonist of serotonin 5-HT2A, 5-HT2B, 5-HT2C, and 5-HT7 receptors. It also has affinity for the 5-HT1A, 5-HT1B, 5-HT1D, 5-HT1F, and 5-HT5A receptors. The compound had entered clinical trials for the treatment of Parkinson's disease; however, further development was halted due to adverse histological abnormalities in rats. It was also investigated for the treatment of hyperprolactinemia (high prolactin levels).
5-hydroxytryptamine (serotonin) receptor 1D, also known as HTR1D, is a 5-HT receptor, but also denotes the human gene encoding it. 5-HT1D acts on the central nervous system, and affects locomotion and anxiety. It also induces vasoconstriction in the brain.
5-hydroxytryptamine (serotonin) 1E receptor (5-HT1E) is a highly expressed human G-protein coupled receptor that belongs to the 5-HT1 receptor family. The human gene is denoted as HTR1E.
5-hydroxytryptamine (serotonin) receptor 1F, also known as HTR1F is a 5-HT1 receptor protein and also denotes the human gene encoding it.
5-Hydroxytryptamine receptor 2B (5-HT2B) also known as serotonin receptor 2B is a protein that in humans is encoded by the HTR2B gene. 5-HT2B is a member of the 5-HT2 receptor family that binds the neurotransmitter serotonin (5-hydroxytryptamine, 5-HT). Like all 5-HT2 receptors, the 5-HT2B receptor is Gq/G11-protein coupled, leading to downstream activation of phospholipase C.
The beta-3 adrenergic receptor (β3-adrenoceptor), also known as ADRB3, is a beta-adrenergic receptor, and also denotes the human gene encoding it.
G-protein coupled receptor 139 (GPC139) is a protein that in humans is encoded by the GPR139 gene. Research has shown that mice with loss of GCP139 experience schizophrenia-like symptomatology that is rescued with the dopamine receptor antagonist haloperidol and the μ-opioid receptor antagonist naltrexone.
Eglumetad is a research drug developed by Eli Lilly and Company, which is being investigated for its potential in the treatment of anxiety and drug addiction. It is a glutamate derived compound and its mode of action implies a novel mechanism.
Tezampanel is a drug originally developed by Eli Lilly which acts as a competitive antagonist of the AMPA and kainate subtypes of the ionotropic glutamate receptor family, with selectivity for the GluR5 subtype of the kainate receptor. It has neuroprotective and anticonvulsant properties, the former of which may, at least in part, occur via blockade of calcium uptake into neurons.
Naluzotan is a serotonergic drug of the phenylpiperazine class that was under investigation by EPIX Pharmaceuticals Inc for the treatment of generalized anxiety disorder and major depressive disorder. It acts as a selective and potent 5-HT1A receptor partial agonist, readily stimulating prolactin responses, though it has also been found to bind to and activate the σ receptor. Naluzotan was well tolerated in clinical trials, with more patients in the control group dropping out due to adverse effects than in the active group in one study. The most frequently reported side effect was headache in 15% of patients. In addition, naluzotan demonstrated significant antidepressant and anxiolytic effects as per the HAM-D and MADRS and the HAM-A, respectively, in some trials, but in others it did not. In the end it was not found to be significantly superior enough to placebo and development was stopped.
LY-379,268 is a drug that is used in neuroscience research, which acts as a potent and selective agonist for the group II metabotropic glutamate receptors (mGluR2/3).
CP-122,288 is a drug which acts as a potent and selective agonist for the 5-HT1B, 5-HT1D and 5-HT1F serotonin receptor subtypes. It is a derivative of the migraine medication sumatriptan, but while CP-122,288 is 40,000 times more potent than sumatriptan as an inhibitor of neurogenic inflammation and plasma protein extravasation, it is only twice as potent as a constrictor of blood vessels. In human trials, CP-122,288 was not found to be effective as a treatment for migraine, but its selectivity for neurogenic anti-inflammatory action over vasoconstriction has made it useful for research into the underlying causes of migraine.
ERA-45 is a synthetic estrogen and a selective agonist of the ERα. It shows 286-fold selectivity for transactivation of the ERα over the ERβ, with EC50 values of 0.37 nM for the ERα (7-fold weaker than estradiol) and 13 nM for the ERβ (20,000-fold weaker than estradiol). However, another found only about 35-fold potency for transactivation of the ERα over the ERβ. The drug has no antagonistic activity at either receptor. ERA-45 induced prostate cancer development in preclinical models when it was given in combination with testosterone, whereas testosterone alone did not do so. In contrast, the selective ERβ agonist ERB-26 was protective against the development of prostate cancer produced by these two drugs. These findings suggest opposing roles of the ERα and ERβ in the prostate gland. The chemical structure of ERa-45 does not appear to have been disclosed.
Amesergide is a serotonin receptor antagonist of the ergoline and lysergamide families related to methysergide which was under development by Eli Lilly and Company for the treatment of a variety of conditions including depression, anxiety, schizophrenia, male sexual dysfunction, migraine, and thrombosis but was never marketed. It reached phase II clinical trials for the treatment of depression, erectile dysfunction, and premature ejaculation prior to the discontinuation of its development.
