5-HT receptors, 5-hydroxytryptamine receptors, or serotonin receptors, are a group of G protein-coupled receptor and ligand-gated ion channels found in the central and peripheral nervous systems. They mediate both excitatory and inhibitory neurotransmission. The serotonin receptors are activated by the neurotransmitter serotonin, which acts as their natural ligand.
Azapirones are a class of drugs used as anxiolytics, antidepressants, and antipsychotics. They are commonly used as add-ons to other antidepressants, such as selective serotonin reuptake inhibitors (SSRIs).
Mianserin, sold under the brand name Tolvon among others, is an atypical antidepressant that is used primarily in the treatment of depression in Europe and elsewhere in the world. It is a tetracyclic antidepressant (TeCA). Mianserin is closely related to mirtazapine, both chemically and in terms of its actions and effects, although there are significant differences between the two drugs.
Opipramol, sold under the brand name Insidon among others, is an anxiolytic and antidepressant that is used throughout Europe. Despite chemically being a tricyclic dibenzazepine (iminostilbene) derivative similar to imipramine, opipramol is not a monoamine reuptake inhibitor like most other tricyclic antidepressants, and instead, uniquely among antidepressants, acts primarily as a sigma receptor agonist. It was developed by Schindler and Blattner in 1961.
Pipamperone, also known as carpiperone and floropipamide or fluoropipamide, and as floropipamide hydrochloride (JAN), is a typical antipsychotic of the butyrophenone family used in the treatment of schizophrenia and as a sleep aid for depression. It is or has been marketed under brand names including Dipiperon, Dipiperal, Piperonil, Piperonyl, and Propitan. Pipamperone was discovered at Janssen Pharmaceutica in 1961, and entered clinical trials in the United States in 1963.
Niaprazine (INN) is a sedative-hypnotic drug of the phenylpiperazine group. It has been used in the treatment of sleep disturbances since the early 1970s in several European countries including France, Italy, and Luxembourg. It is commonly used with children and adolescents on account of its favorable safety and tolerability profile and lack of abuse potential.
Tenocyclidine (TCP) is a dissociative anesthetic with psychostimulant effects. It was discovered by a team at Parke-Davis in the late 1950s. It is similar in effects to phencyclidine (PCP) but is considerably more potent. TCP has slightly different binding properties to PCP, with more affinity for the NMDA receptors, but less affinity for the sigma receptors. Because of its high affinity for the PCP site of the NMDA receptor complex, the 3H radiolabelled form of TCP is widely used in research into NMDA receptors.
Siramesine is a sigma receptor agonist, selective for the σ2 subtype. In animal studies, siramesine has been shown to produce anxiolytic and antidepressant effects. It was developed by the pharmaceutical company H Lundbeck for the treatment of anxiety, although development was discontinued after clinical trials showed a lack of efficacy in humans.
Rimcazole is an antagonist of the sigma receptor as well as a dopamine reuptake inhibitor. Sigma receptors are thought to be involved in the drug psychosis that can be induced by some drugs such as phencyclidine and cocaine, and rimcazole was originally researched as a potential antipsychotic with a different mechanism of action to traditional antipsychotic drugs. Trials proved inconclusive and rimcazole was not pursued for this application, but other sigma antagonists continue to be researched for a variety of potential applications. Rimcazole has been shown to reduce the effects of cocaine, and analogues of rimcazole have been shown to be highly effective at blocking the convulsions caused by cocaine overdose in animal models.
RS-67,333 is a drug which has been investigated as a potential rapid-acting antidepressant, nootropic, and treatment for Alzheimer's disease. It is a high-affinity 5-HT4 receptor partial agonist, as well as a sigma receptor ligand of both subtypes to a lesser extent.
Cyamemazine (Tercian), also known as cyamepromazine, is a typical antipsychotic drug of the phenothiazine class which was introduced by Theraplix in France in 1972 and later in Portugal as well.
Sultopride (trade names Barnetil, Barnotil, Topral) is an atypical antipsychotic of the benzamide chemical class used in Europe, Japan, and Hong Kong for the treatment of schizophrenia. It was launched by Sanofi-Aventis in 1976. Sultopride acts as a selective D2 and D3 receptor antagonist. It has also been shown to have clinically relevant affinity for the GHB receptor as well, a property it shares in common with amisulpride and sulpiride.
5-Iodowillardiine is a selective agonist for the kainate receptor, with only limited effects at the AMPA receptor. It is selective for kainate receptors composed of GluR5 subunits. It is an excitotoxic neurotoxin in vivo, but has proved highly useful for characterising the subtypes and function of the various kainate receptors in the brain and spinal cord.
Igmesine (JO-1,784) is a sigma receptor agonist (IC50 = 39 nM (rat brain)). It has neuroprotective and antidepressant-like effects in animal studies, as well as nootropic effects in models of age-related cognitive decline. In two phase II clinical trials, igmesine was found to be effective in the treatment of depression and was as active as the comparator fluoxetine. However, in a large phase III clinical trial, igmesine failed to show significant effectiveness for depression. The drug has not been developed further.
Metapramine is a tricyclic antidepressant (TCA) developed by Rhone Poulenc that was introduced for the treatment of depression in France in 1984. In addition to its efficacy against affective disorders, it also has analgesic properties, and may be useful in the treatment of pain.
Dazopride (AHR-5531) is an antiemetic and gastroprokinetic agent of the benzamide class which was never marketed. It acts as a 5-HT3 receptor antagonist and 5-HT4 receptor agonist. In addition to its gastrointestinal effects, dazopride facilitates learning and memory in mice.
Umespirone (KC-9172) is a drug of the azapirone class which possesses anxiolytic and antipsychotic properties. It behaves as a 5-HT1A receptor partial agonist (Ki = 15 nM), D2 receptor partial agonist (Ki = 23 nM), and α1-adrenoceptor receptor antagonist (Ki = 14 nM), and also has weak affinity for the sigma receptor (Ki = 558 nM). Unlike many other anxiolytics and antipsychotics, umespirone produces minimal sedation, cognitive/memory impairment, catalepsy, and extrapyramidal symptoms.
Clocapramine, also known as 3-chlorocarpipramine, is an atypical antipsychotic of the iminodibenzyl class which was introduced in Japan in 1974 by Yoshitomi for the treatment of schizophrenia. In addition to psychosis, clocapramine has also been used to augment antidepressants in the treatment of anxiety and panic.
PD 144418 or 1,2,3,6-tetrahydro-5-[3-(4-methylphenyl)-5-isoxazolyl]-1-propylpyridine is a potent and selective ligand for the sigma-1 receptor, with a reported binding affinity of Ki = 0.08 ± 0.01 nM, and 17 212 times selectivity over the sigma-2 receptor.
Panamesine (INN; developmental code name EMD-57455) is a sigma receptor antagonist that was under development by Merck as a potential antipsychotic for the treatment of schizophrenia in the 1990s but was never marketed. It is a selective antagonist of both sigma receptor subtypes, the σ1 and σ2 receptors (IC50 = 6 nM). In addition, the major metabolite of the drug, EMD-59983, has high affinity for the sigma receptors (IC50 = 24 nM) and the dopamine D2 (IC50 = 23 nM) and D3 receptors, with potent antidopaminergic activity. Panamesine reached phase II clinical trials for schizophrenia prior to the discontinuation of its development.
↑ Snyder SH, Largent BL (1989). "Receptor mechanisms in antipsychotic drug action: focus on sigma receptors". The Journal of Neuropsychiatry and Clinical Neurosciences. 1 (1): 7–15. doi:10.1176/jnp.1.1.7. PMID2577720.
↑ Matheson GK, Guthrie D, Bauer C, Knowles A, White G, Ruston C (January 1991). "Sigma receptor ligands alter concentrations of corticosterone in plasma in the rat". Neuropharmacology. 30 (1): 79–87. doi:10.1016/0028-3908(91)90046-E. PMID1675451. S2CID29702968.
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