Phencyclidine or phenylcyclohexyl piperidine (PCP), also known as angel dust among other names, is a dissociative anesthetic mainly used recreationally for its significant mind-altering effects. PCP may cause hallucinations, distorted perceptions of sounds, and violent behavior. As a recreational drug, it is typically smoked, but may be taken by mouth, snorted, or injected. It may also be mixed with cannabis or tobacco.
The atypical antipsychotics (AAP), also known as second generation antipsychotics (SGAs) and serotonin–dopamine antagonists (SDAs), are a group of antipsychotic drugs largely introduced after the 1970s and used to treat psychiatric conditions. Some atypical antipsychotics have received regulatory approval for schizophrenia, bipolar disorder, irritability in autism, and as an adjunct in major depressive disorder.
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.
Dizocilpine (INN), also known as MK-801, is a pore blocker of the N-Methyl-D-aspartate (NMDA) receptor, a glutamate receptor, discovered by a team at Merck in 1982. Glutamate is the brain's primary excitatory neurotransmitter. The channel is normally blocked with a magnesium ion and requires depolarization of the neuron to remove the magnesium and allow the glutamate to open the channel, causing an influx of calcium, which then leads to subsequent depolarization. Dizocilpine binds inside the ion channel of the receptor at several of PCP's binding sites thus preventing the flow of ions, including calcium (Ca2+), through the channel. Dizocilpine blocks NMDA receptors in a use- and voltage-dependent manner, since the channel must open for the drug to bind inside it. The drug acts as a potent anti-convulsant and probably has dissociative anesthetic properties, but it is not used clinically for this purpose because of the discovery of brain lesions, called Olney's lesions (see below), in laboratory rats. Dizocilpine is also associated with a number of negative side effects, including cognitive disruption and psychotic-spectrum reactions. It inhibits the induction of long term potentiation and has been found to impair the acquisition of difficult, but not easy, learning tasks in rats and primates. Because of these effects of dizocilpine, the NMDA receptor pore blocker ketamine is used instead as a dissociative anesthetic in human medical procedures. While ketamine may also trigger temporary psychosis in certain individuals, its short half-life and lower potency make it a much safer clinical option. However, dizocilpine is the most frequently used uncompetitive NMDA receptor antagonist in animal models to mimic psychosis for experimental purposes.
Memantine is a medication used to slow the progression of moderate-to-severe Alzheimer's disease. It is taken by mouth.
Orphenadrine is an anticholinergic drug of the ethanolamine antihistamine class; it is closely related to diphenhydramine. It is a muscle relaxant that is used to treat muscle pain and to help with motor control in Parkinson's disease, but has largely been superseded by newer drugs. This substance is considered a dirty drug due to its multiple mechanism of action in different pathways. It was discovered and developed in the 1940s.
Nicergoline, sold under the brand name Sermion among others, is an ergot derivative used to treat senile dementia and other disorders with vascular origins. Internationally it has been used for frontotemporal dementia as well as early onset in Lewy body dementia and Parkinson's dementia. It decreases vascular resistance and increases arterial blood flow in the brain, improving the utilization of oxygen and glucose by brain cells. It has similar vasoactive properties in other areas of the body, particularly the lungs. Unlike many other ergolines, such as ergotamine, nicergoline is not associated with cardiac fibrosis.
meta-Chlorophenylpiperazine (mCPP) is a psychoactive drug of the phenylpiperazine class. It was initially developed in the late-1970s and used in scientific research before being sold as a designer drug in the mid-2000s. It has been detected in pills touted as legal alternatives to illicit stimulants in New Zealand and pills sold as "ecstasy" in Europe and the United States.
NMDA receptor antagonists are a class of drugs that work to antagonize, or inhibit the action of, the N-Methyl-D-aspartate receptor (NMDAR). They are commonly used as anesthetics for animals and humans; the state of anesthesia they induce is referred to as dissociative anesthesia.
The serotonin 1A receptor is a subtype of serotonin receptor, or 5-HT receptor, that binds serotonin, also known as 5-HT, a neurotransmitter. 5-HT1A is expressed in the brain, spleen, and neonatal kidney. It is a G protein-coupled receptor (GPCR), coupled to the Gi protein, and its activation in the brain mediates hyperpolarisation and reduction of firing rate of the postsynaptic neuron. In humans, the serotonin 1A receptor is encoded by the HTR1A gene.
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.
Remacemide is a drug which acts as a low-affinity NMDA antagonist with sodium channel blocking properties. It has been studied for the treatment of acute ischemic stroke, epilepsy, Huntington's disease, and Parkinson's disease.
Sarpogrelate is a drug which acts as an antagonist at the 5HT2A and 5-HT2B receptors. It blocks serotonin-induced platelet aggregation, and has applications in the treatment of many diseases including diabetes mellitus, Buerger's disease, Raynaud's disease, coronary artery disease, angina pectoris, and atherosclerosis.
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.
Indeloxazine (INN) is an antidepressant and cerebral activator that was marketed in Japan and South Korea by Yamanouchi Pharmaceutical Co., Ltd for the treatment of psychiatric symptoms associated with cerebrovascular diseases, namely depression resulting from stroke, emotional disturbance, and avolition. It was marketed from 1988 to 1998, when it was removed from the market reportedly for lack of effectiveness.
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.
Volinanserin (INN) is a highly selective 5-HT2A receptor antagonist that is frequently used in scientific research to investigate the function of the 5-HT2A receptor. It was also tested in clinical trials as a potential antipsychotic, antidepressant, and treatment for insomnia but was never marketed.
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.
SB-206553 is a drug which acts as a mixed antagonist for the 5-HT2B and 5-HT2C serotonin receptors. It has anxiolytic properties in animal studies and interacts with a range of other drugs. It has also been shown to act as a positive allosteric modulator of α7 nicotinic acetylcholine receptors. Modified derivatives of SB-206553 have been used to probe the structure of the 5-HT2B receptor.
Neboglamine (INN), formerly known as nebostinel, is a positive allosteric modulator of the glycine site of the NMDA receptor which is under investigation for Rottapharm for the treatment of schizophrenia and cocaine dependence. It shows cognition- and memory-enhancing effects in animal models. As of June 2015, it is in phase II clinical trials for both schizophrenia and cocaine abuse.
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