The 5-HT2A receptor is a subtype of the 5-HT2 receptor that belongs to the serotonin receptor family and is a G protein-coupled receptor (GPCR). The 5-HT2A receptor is a cell surface receptor, but has several intracellular locations. 5-HT is short for 5-hydroxy-tryptamine or serotonin. This is the main excitatory receptor subtype among the GPCRs for serotonin, although 5-HT2A may also have an inhibitory effect on certain areas such as the visual cortex and the orbitofrontal cortex. This receptor was first noted for its importance as a target of serotonergic psychedelic drugs such as LSD and psilocybin mushrooms. Later it came back to prominence because it was also found to be mediating, at least partly, the action of many antipsychotic drugs, especially the atypical ones.
Tandospirone is an anxiolytic and antidepressant drug used in China and Japan, where it is marketed by Dainippon Sumitomo Pharma. It is a member of the azapirone class of drugs and is closely related to other azapirones like buspirone and gepirone.
The 5HT6 receptor is a subtype of 5HT receptor that binds the endogenous neurotransmitter serotonin (5-hydroxytryptamine, 5HT). It is a G protein-coupled receptor (GPCR) that is coupled to Gs and mediates excitatory neurotransmission. HTR6 denotes the human gene encoding for the receptor.
Nisoxetine, originally synthesized in the Lilly research laboratories during the early 1970s, is a potent and selective inhibitor for the reuptake of norepinephrine (noradrenaline) into synapses. It currently has no clinical applications in humans, although it was originally researched as an antidepressant. Nisoxetine is now widely used in scientific research as a standard selective norepinephrine reuptake inhibitor. It has been used to research obesity and energy balance, and exerts some local analgesia effects.
Blonanserin, sold under the brand name Lonasen, is a relatively new atypical antipsychotic commercialized by Dainippon Sumitomo Pharma in Japan and Korea for the treatment of schizophrenia. Relative to many other antipsychotics, blonanserin has an improved tolerability profile, lacking side effects such as extrapyramidal symptoms, excessive sedation, or hypotension. As with many second-generation (atypical) antipsychotics it is significantly more efficacious in the treatment of the negative symptoms of schizophrenia compared to first-generation (typical) antipsychotics such as haloperidol.
SB-258585 is a drug which is used in scientific research. It acts as a potent, selective and orally active 5-HT6 receptor antagonist, with a Ki of 8.9nM. It is used in its 125I radiolabelled form to map the distribution of 5-HT6 receptors in the brain.
SB-399885 is a drug which is used in scientific research. It acts as a potent, selective and orally active 5-HT6 receptor antagonist, with a Ki of 9.0nM. SB-399885 and other 5-HT6 antagonists show nootropic effects in animal studies, as well as antidepressant and anxiolytic effects which are comparable to and synergistic with drugs such as imipramine and diazepam, and have been proposed as potential novel treatments for cognitive disorders such as schizophrenia and Alzheimer's disease.
SB-357134 is a drug which is used in scientific research. It acts as a potent, selective and orally active 5-HT6 receptor antagonist. SB-357134 and other 5-HT6 antagonists show nootropic effects in animal studies, and have been proposed as potential novel treatments for cognitive disorders such as schizophrenia and Alzheimer's disease.
SB-271046 is a drug which is used in scientific research. It was one of the first selective 5-HT6 receptor antagonists to be discovered, and was found through high-throughput screening of the SmithKline Beecham Compound Bank using cloned 5-HT6 receptors as a target, with an initial lead compound being developed into SB-271046 through a structure-activity relationship (SAR) study. SB-271046 was found to be potent and selective in vitro and had good oral bioavailability in vivo, but had poor penetration across the blood–brain barrier, so further SAR work was then conducted, which led to improved 5-HT6 antagonists such as SB-357,134 and SB-399,885.
Ro 04-6790 is a drug, developed by Hoffmann–La Roche, which has applications in scientific research. It acts as a potent and selective receptor antagonist for the 5-HT6 serotonin receptor subtype, with little or no affinity at other receptors. In common with other drugs of this class, Ro 04-6790 has nootropic effects in animals, and reduces the amnesia produced by memory-impairing drugs such as dizocilpine and scopolamine.
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.
Epix Pharmaceuticals Inc was a pharmaceutical company based in Lexington, Massachusetts.
Capeserod (INN; development code SL65.0155) is a selective 5-HT4 receptor partial agonist with Ki = 0.6 nM and IA = 40–50% (relative to serotonin). It potently enhances cognition, learning, and memory, and also possesses antidepressant effects. Capeserod was in phase II clinical trials around 2004–2006 for the treatment of memory deficits and dementia but no new information has surfaced since and it appears to have been abandoned.
Intepirdine (INN; developmental codes SB-742457, RVT-101) is a selective 5-HT6 receptor antagonist with potential cognition, memory, and learning-enhancing effects. It was under development by GlaxoSmithKline for the treatment of Alzheimer's disease and demonstrated some preliminary efficacy in phase II clinical trials. GSK chose not to continue development and sold the rights to Axovant Sciences for $5 million in December 2014.
F-15,599, also known as NLX-101, is a potent and selective 5-HT1A receptor full agonist. It displays functional selectivity by strongly activating 5-HT1A receptors in the postsynaptic prefrontal cortex while having little effect on somatodendritic autoreceptors in the raphe nucleus. As a result, it has been touted as a preferential postsynaptic 5-HT1A receptor agonist and has been investigated as a novel potential antidepressant.
PRX-08066 is a drug discovered and developed by Predix Pharmaceuticals [Dale S. Dhanoa et al. Patent US 7,030,240 B2], which acts as a potent and selective antagonist at the serotonin 5-HT2B receptor, with a 5-HT2Bbinding affinity (Ki) of 3.4nM, and high selectivity over the closely related 5-HT2A and 5-HT2C receptors and other receptor targets. PRX-08066 and other selective 5-HT2B antagonists are being researched for the treatment of pulmonary arterial hypertension, following the discovery that the potent 5-HT2B agonist norfenfluramine produces pulmonary arterial hypertension and subsequent heart valve damage. In animal studies, PRX-08066 has been found to reduce several key indicators of pulmonary arterial hypertension and improved cardiac output, with similar efficacy to established drugs for this condition such as bosentan, sildenafil, beraprost and iloprost. It is also being researched for potential anti-cancer applications, due to its ability to inhibit fibroblast activation.
PRX-03140 is a partial agonist (18% relative to 5-HT) of the 5-HT4 receptor that was developed by EPIX Pharmaceuticals for Alzheimer's disease.
5-HT2C receptor agonists are a class of drugs that activate 5-HT2C receptors. They have been investigated for the treatment of a number of conditions including obesity, psychiatric disorders, sexual dysfunction and urinary incontinence.
AVN-211 (CD-008-0173) is a drug which acts as a highly selective 5-HT6 receptor antagonist and is under development by Avineuro Pharmaceuticals for the treatment of schizophrenia. In early 2011, it successfully completed phase IIa clinical trials, with benefits on positive symptoms and some procognitive effects observed, and in mid 2013, phase IIb clinical trials for schizophrenia began. Avineuro Pharmaceuticals has also expressed intention to start clinical trials of AVN-211 for Alzheimer's disease in 2015.
JNJ-18038683 is a potent and selective antagonist of the 5HT7 serotonin receptor discovered by Johnson & Johnson. It has nootropic and antidepressant effects in both animal and human studies and has progressed to Phase II trials as an adjunctive treatment for improving cognition and mood in stable bipolar disorder; it has been found to reduce REM sleep (the lightest stage of sleep, elevated in depression) in humans and block circadian rhythm phase-shift advances in mice.
