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| Formula | C16H25NS |
| Molar mass | 263.44 g·mol−1 |
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Gacyclidine [1] (GK-11, OTO-313) [2] [3] is a psychoactive drug which acts as a dissociative via functioning as a non-competitive NMDA receptor antagonist. It is closely related to phencyclidine (PCP), and specifically, is a derivative of tenocyclidine (TCP). [4] [5]
Gacyclidine is a psychoactive drug that was used for helping with body trauma in humans. While seeing most tests on animals, it was never used commercially to the degree as other painkillers or psychoactive drugs. While Gacyclidine has been used in numerous tests dating back to 2012, these tests did not provide fruitful results that would push the future of the drug into a different direction.
The 1,2-addition of 2-methylcyclohexanone (I) with 2-thienyl lithium (II) or 2-thienyl magnesium bromide (III) gives cyclohexanol (IV) as a diastereomeric mixture, which was treated with sodium azide (NaN3) in trichloroacetic acid to yield the azide (V). The reduction of (V) with lithium aluminium hydride (LiAlH4) or Raney nickel in isopropanol affords the corresponding amine (VI), preferentially with the cis-configuration. Finally, this compound is dialkylated with 1,5-dibromopentane (VII) by means of potassium carbonate (K2CO3) in acetonitrile to provide the target compound as a diastereomeric mixture. [6]
Gacyclidine's original purpose was for helping with human body trauma, specifically spine and brain trauma. Tests were done on animals to see how their bodies would react to the different drugs and see how that information could be applied to humans. Gacyclidine is used to reduce damage to the brain or spinal cord, hence a treatment for tinnitus, stroke, trauma, and convulsion. As a psychoactive drug, alteration of perception is what makes this substance of use. The use of this product derives in medical usage. It is recommended that the prescriptive drug be used before such injuries, but it could be of use after the injury has occurred. A lipid-based intratympanic formulation of gacyclidine (OTO-313) has been studied as an potential therapy for the treatment of tinnitus. [3]
Testing of Gacyclidine was performed on animals in a study. In concluding hours (18-96 h) no necrotic neurons were discovered in animals with dosages of 1, 5, 10, 20 milligrams of Gacyclidine. At 20 milligrams the presence of a few cytoplasmic vacuoles were present. In a study conducted to find possible neurotoxicity in dosages, scientists tested the effects of Gacyclidine in comparison to MK-801 (dizocilpine) and CNS-1102, and finalized more positive effects on animals from Gacyclidine. When given MK-801 at dosages of 1 or 5 milligrams of Gacyclidine, effects were harmless and behaved similarly to untreated animals. At dosages between 5 and 10 milligrams, the animals began to experience behaviors of tremors, sedation and exophthalmos. With CNS-1102, at all doses tested, the animals exhibited some excitation. At the highest doses (10 and 20 milligrams) they suffered from severe akinesia 1 hour after drug administration. Animals that received 1 or 5 milligrams of Gacyclidine or its enantiomers behave similarly to untreated animals. At the highest doses (10 and 20 milligrams), the animals began to show some signs of excitation. For all doses, the recovery period was always better with Gacyclidine and its enantiomers than with MK-801 or CNS-1102. The days after the testing, labs observed electron microscopy in the 20-milligram group. During observation small lesions were labeled as cytoplasmic or intramitochondrial vacuoles. In addition, no neuronal or glial alterations, such as astrocytic swelling or microglial activation, were seen that could suggest a short-term toxic event had occurred. Further concluding observations, current evidence indicates that the possibility of a short-term toxicity, would be totally reversible. Likewise, any long-term toxicity would become evident after 4 days. But, the evidence in total strongly suggests that Gacyclidine and its enantiomers are, at least, far less neurotoxic than MK-801.
With the use of this drug, motor skills have significantly improved upon use, as it is the antagonist to the NMDA receptor. Gacyclidine is able to reduce calcium getting into cells. While animal test results showed potential in the rats, human tests showed slight improvement to the condition of patients. Outside of results seen in animals like potential trauma assistance and pain relief, there is little to no proof that there will be any clinical benefits in the future of Gacyclidine.
The results of Gacyclidine are helpful in reducing the size of the lesion and enhancing the functional parameters after injury. Gacyclidine also increases behavioral parameters and neuronal survival in traumatic brain injury models. When gacyclidine is administered 0 to 30 minutes after injury, optimum protection is obtained. It is therefore concluded that Gacyclidine exhibits neuroprotective effects close to those of other antagonists of the NMDA receptor, with the benefit of being slightly less neuroprotective.
Gacyclidine being a psychoactive drug and its chemical makeup have the potential to become a very addictive drug when combined in certain formulas. This resulted in Gacyclidine falling under the list of drugs that were placed under the Controlled Substances Act which sought to control the distribution of certain drugs such psychoactive drugs, depressants, and narcotics.
Phencyclidine or phenylcyclohexyl piperidine (PCP), also known in its use as a street drug 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.
Dizocilpine (INN), also known as MK-801, is a pore blocker of the 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.
Olney's lesions, also known as NMDA receptor antagonist neurotoxicity (NAT), is a form of brain damage observed in rats and certain other model animals exposed to large quantities of psychoactive drugs that inhibit the normal operation of the neuronal NMDA receptor. Such lesions are common in anesthesia, as well as certain psychiatric treatments.
Neuroprotection refers to the relative preservation of neuronal structure and/or function. In the case of an ongoing insult the relative preservation of neuronal integrity implies a reduction in the rate of neuronal loss over time, which can be expressed as a differential equation. It is a widely explored treatment option for many central nervous system (CNS) disorders including neurodegenerative diseases, stroke, traumatic brain injury, spinal cord injury, and acute management of neurotoxin consumption. Neuroprotection aims to prevent or slow disease progression and secondary injuries by halting or at least slowing the loss of neurons. Despite differences in symptoms or injuries associated with CNS disorders, many of the mechanisms behind neurodegeneration are the same. Common mechanisms of neuronal injury include decreased delivery of oxygen and glucose to the brain, energy failure, increased levels in oxidative stress, mitochondrial dysfunction, excitotoxicity, inflammatory changes, iron accumulation, and protein aggregation. Of these mechanisms, neuroprotective treatments often target oxidative stress and excitotoxicity—both of which are highly associated with CNS disorders. Not only can oxidative stress and excitotoxicity trigger neuron cell death but when combined they have synergistic effects that cause even more degradation than on their own. Thus limiting excitotoxicity and oxidative stress is a very important aspect of neuroprotection. Common neuroprotective treatments are glutamate antagonists and antioxidants, which aim to limit excitotoxicity and oxidative stress respectively.
Armodafinil (trade name Nuvigil) is the enantiopure compound of the eugeroic modafinil (Provigil). It consists of only the (R)-(−)-enantiomer of the racemic modafinil. Armodafinil is produced by the pharmaceutical company Cephalon Inc. and was approved by the U.S. Food and Drug Administration (FDA) in June 2007. In 2016, the FDA granted Mylan rights for the first generic version of Cephalon's Nuvigil to be marketed in the U.S.
Acamprosate, sold under the brand name Campral, is a medication used along with counseling to treat alcohol use disorder.
Phenibut, sold under the brand names Anvifen, Fenibut, and Noofen among others, is a central nervous system depressant with anxiolytic effects, and is used to treat anxiety, insomnia, and for a variety of other indications. It is usually taken by mouth as a tablet, but may be given intravenously.
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 human and non-human animals; the state of anesthesia they induce is referred to as dissociative anesthesia.
Aptiganel is an unsuccessful drug candidate which acts as a noncompetitive NMDA antagonist, and that was under development by Cambridge Neuroscience, Inc as a treatment for stroke. It has neuroprotective effects and was researched for potential use in the treatment of stroke, but despite positive results in animal studies, human trials showed limited efficacy, as well as undesirable side effects such as sedation and hallucinations, and clinical development was ultimately not continued.
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.
Neramexane is a drug related to memantine, which acts as an NMDA antagonist and has neuroprotective effects. It is being developed for various possible applications, including treatment of tinnitus, Alzheimer's disease, drug addiction and as an analgesic. Animal studies have also suggested antidepressant and nootropic actions, so there are a wide range of potential applications this drug may be used for. It also acts as a nicotinic acetylcholine receptor antagonist.
Benocyclidine, also known as benzo
Arylcyclohexylamines, also known as arylcyclohexamines or arylcyclohexanamines, are a chemical class of pharmaceutical, designer, and experimental drugs.
3-Methoxyphencyclidine (3-MeO-PCP) is a dissociative hallucinogen of the arylcyclohexylamine class related to phencyclidine (PCP) which has been sold online as a designer drug. It acts mainly as an NMDA receptor antagonist, though it has also been found to interact with the sigma σ1 receptor and the serotonin transporter. The drug does not possess any opioid activity nor does it act as a dopamine reuptake inhibitor.
4-Methoxyphencyclidine is a dissociative anesthetic drug that has been sold online as a research chemical. The synthesis of 4-MeO-PCP was first reported in 1965 by the Parke-Davis medicinal chemist Victor Maddox. A 1999 review published by a chemist using the pseudonym John Q. Beagle suggested the potency of 4-MeO-PCP in man was reduced relative to PCP, two years later Beagle published a detailed description of the synthesis and qualitative effects of 4-MeO-PCP, which he said possessed 70% the potency of PCP. 4-MeO-PCP was the first arylcyclohexylamine research chemical to be sold online, it was introduced in late 2008 by a company trading under the name CBAY and was followed by several related compounds such as 3-MeO-PCP and methoxetamine. 4-MeO-PCP has lower affinity for the NMDA receptor than PCP, but higher affinity than ketamine, it is orally active in a dosage range similar to ketamine, with some users requiring doses in excess of 100 mg for desired effects. Users have reported substantial differences in active dose, these discrepancies can be partially explained by the presence of unreacted PCC and other impurities in samples sold on the grey market. 4-MeO-PCP has Ki values of 404 nM for the NMDA receptor, 713 nM for the norepinephrine transporter, 844 nM for the serotonin transporter, 296 nM for the σ1 receptor and 143 nM for the σ2 receptor.
Methoxetamine, abbreviated as MXE, is a dissociative hallucinogen that has been sold as a designer drug. It differs from many dissociatives such as ketamine and phencyclidine (PCP) that were developed as pharmaceutical drugs for use as general anesthetics in that it was designed specifically to increase the antidepressant effects of ketamine.
Traxoprodil is a drug developed by Pfizer which acts as an NMDA antagonist, selective for the NR2B subunit. It has neuroprotective, analgesic, and anti-Parkinsonian effects in animal studies. Traxoprodil has been researched in humans as a potential treatment to lessen the damage to the brain after stroke, but results from clinical trials showed only modest benefit. The drug was found to cause EKG abnormalities and its clinical development was stopped. More recent animal studies have suggested traxoprodil may exhibit rapid-acting antidepressant effects similar to those of ketamine, although there is some evidence for similar psychoactive side effects and abuse potential at higher doses, which might limit clinical acceptance of traxoprodil for this application.
HA-966 or (±)-3-amino-1-hydroxy-pyrrolidin-2-one is a molecule used in scientific research as a glycine receptor and NMDA receptor antagonist / low efficacy partial agonist. It has neuroprotective and anticonvulsant, anxiolytic, antinociceptive and sedative / hypnotic effects in animal models. Pilot human clinical trials in the early 1960s showed that HA-966 appeared to benefit patients with tremors of extrapyramidal origin.
3-Hydroxyphencyclidine (3-HO-PCP) is a dissociative of the arylcyclohexylamine class related to phencyclidine (PCP) that has been sold online as a designer drug.
3-Methyl-PCPy (3-Me-PCPy) is an arylcyclohexylamine derivative with an unusual spectrum of pharmacological effects, acting as both a potent NMDA antagonist and also a triple reuptake inhibitor which inhibits reuptake of all three monoamine neurotransmitters serotonin, dopamine and noradrenaline. It also acts as a high affinity sigma receptor ligand, selective for the σ2 subtype. It produces both stimulant and dissociative effects in animal behavioural studies.
