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Arylcyclohexylamines, also known as arylcyclohexamines or arylcyclohexanamines, are a
chemical class Chemical classification systems attempt to classify elements or compounds according to certain chemical functional or structural properties. Whereas the structural properties are largely intrinsic, functional properties and the derived classificat ...
of
pharmaceutical A medication (also called medicament, medicine, pharmaceutical drug, medicinal drug or simply drug) is a drug used to diagnose, cure, treat, or prevent disease. Drug therapy (pharmacotherapy) is an important part of the medical field and re ...
,
designer A designer is a person who plans the form or structure of something before it is made, by preparing drawings or plans. In practice, anyone who creates tangible or intangible objects, products, processes, laws, games, graphics, services, or exp ...
, and
experimental drug An experimental drug is a medicinal product (a drug or vaccine) that has not yet received approval from governmental regulatory authorities for routine use in human or veterinary medicine. A medicinal product may be approved for use in one diseas ...
s.


History

Phencyclidine 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 perceptio ...
(PCP) is believed to be the first arylcyclohexylamine with recognized anesthetic properties, but several arylcyclohexylamines were described before PCP in the scientific literature, beginning with PCA (1-phenylcyclohexan-1-amine) the synthesis of which was first published in 1907. PCE was reported in 1953 and PCMo (4-(1-phenyl-cyclohexyl)-morpholine see chart below for figure) in 1954, with PCMo described as a potent sedative. Arylcyclohexylamine anesthetics were intensively investigated at
Parke-Davis Parke-Davis is a subsidiary of the pharmaceutical company Pfizer. Although Parke, Davis & Co. is no longer an independent corporation, it was once America's oldest and largest drug maker, and played an important role in medical history. In 1970 ...
, beginning with the 1956 synthesis of
phencyclidine 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 perceptio ...
and later the related compound
ketamine Ketamine is a dissociative anesthetic used medically for induction and maintenance of anesthesia. It is also used as a recreational drug. It is one of the safest anesthetics, as, in contrast with opiates, ether, and propofol, it suppresses ne ...
. The 1970s saw the debut of these compounds, especially PCP and its analogues, as illicitly used
recreational drugs Recreation is an activity of leisure, leisure being discretionary time. The "need to do something for recreation" is an essential element of human biology and psychology. Recreational activities are often done for enjoyment, amusement, or pleasur ...
due to their
dissociative Dissociatives, colloquially dissos, are a subclass of hallucinogens which distort perception of sight and sound and produce feelings of detachment – dissociation – from the environment and/or self. Although many kinds of drugs are capable of ...
hallucinogen Hallucinogens are a large, diverse class of psychoactive drugs that can produce altered states of consciousness characterized by major alterations in thought, mood, and perception as well as other changes. Most hallucinogens can be categorized ...
ic and
euphoriant Euphoria ( ) is the experience (or affect) of pleasure or excitement and intense feelings of well-being and happiness. Certain natural rewards and social activities, such as aerobic exercise, laughter, listening to or making music and danci ...
effects. Since that time, the class has been expanded by
scientific research The scientific method is an empirical method for acquiring knowledge that has characterized the development of science since at least the 17th century (with notable practitioners in previous centuries; see the article history of scientific m ...
into
stimulant Stimulants (also often referred to as psychostimulants or colloquially as uppers) is an overarching term that covers many drugs including those that increase activity of the central nervous system and the body, drugs that are pleasurable and inv ...
,
analgesic An analgesic drug, also called simply an analgesic (American English), analgaesic (British English), pain reliever, or painkiller, is any member of the group of drugs used to achieve relief from pain (that is, analgesia or pain management). It ...
, and
neuroprotective Neuroprotection refers to the relative preservation of neuronal structure and/or function. In the case of an ongoing insult (a neurodegenerative insult) the relative preservation of neuronal integrity implies a reduction in the rate of neuronal los ...
agents, and also by
clandestine Clandestine may refer to: * Secrecy, the practice of hiding information from certain individuals or groups, perhaps while sharing it with other individuals * Clandestine operation, a secret intelligence or military activity Music and entertainme ...
chemist A chemist (from Greek ''chēm(ía)'' alchemy; replacing ''chymist'' from Medieval Latin ''alchemist'') is a scientist trained in the study of chemistry. Chemists study the composition of matter and its properties. Chemists carefully describe th ...
s in search of novel
recreational drug Recreational drug use indicates the use of one or more psychoactive drugs to induce an altered state of consciousness either for pleasure or for some other casual purpose or pastime by modifying the perceptions and emotions of the user. When a ...
s.


Structure

An arylcyclohexylamine is composed of a
cyclohexylamine Cyclohexylamine is an organic compound, belonging to the aliphatic amine class. It is a colorless liquid, although, like many amines, samples are often colored due to contaminants. It has a fishy odor and is miscible with water. Like other amines, ...
unit with an
aryl In organic chemistry, an aryl is any functional group or substituent derived from an aromatic ring, usually an aromatic hydrocarbon, such as phenyl and naphthyl. "Aryl" is used for the sake of abbreviation or generalization, and "Ar" is used as ...
moiety Moiety may refer to: Chemistry * Moiety (chemistry), a part or functional group of a molecule ** Moiety conservation, conservation of a subgroup in a chemical species Anthropology * Moiety (kinship), either of two groups into which a society is ...
attachment. The aryl group is positioned
geminal In chemistry, the descriptor geminal () refers to the relationship between two atoms or functional groups that are attached to the same atom. A geminal diol, for example, is a diol (a molecule that has two alcohol functional groups) attached to ...
to the
amine In chemistry, amines (, ) are compounds and functional groups that contain a basic nitrogen atom with a lone pair. Amines are formally derivatives of ammonia (), wherein one or more hydrogen atoms have been replaced by a substituen ...
. In the simplest cases, the aryl moiety is typically a
phenyl ring In organic chemistry, the phenyl group, or phenyl ring, is a cyclic group of atoms with the formula C6 H5, and is often represented by the symbol Ph. Phenyl group is closely related to benzene and can be viewed as a benzene ring, minus a hydrogen ...
, sometimes with additional substitution. The amine is usually not primary; secondary amines such as methylamino or ethylamino, or tertiary cycloalkylamines such as piperidino and pyrrolidino, are the most commonly encountered ''N''-substituents.


Pharmacology

Arylcyclohexylamines varyingly possess
NMDA receptor antagonist 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 ...
ic,
dopamine reuptake inhibitor A dopamine reuptake inhibitor (DRI) is a class of drug which acts as a reuptake inhibitor of the monoamine neurotransmitter dopamine by blocking the action of the dopamine transporter (DAT). Reuptake inhibition is achieved when extracellular dopa ...
y, and
μ-opioid receptor The μ-opioid receptors (MOR) are a class of opioid receptors with a high affinity for enkephalins and beta-endorphin, but a low affinity for dynorphins. They are also referred to as μ(''mu'')-opioid peptide (MOP) receptors. The prototypical Π...
agonist An agonist is a chemical that activates a receptor to produce a biological response. Receptors are cellular proteins whose activation causes the cell to modify what it is currently doing. In contrast, an antagonist blocks the action of the ago ...
ic properties. Additionally, σ receptor agonistic, nACh receptor antagonistic, and D2 receptor agonistic actions have been reported for some of these agents. Antagonism of the NMDA receptor confers anesthetic, anticonvulsant, neuroprotective, and dissociative effects; blockade of the
dopamine transporter The dopamine transporter (also dopamine active transporter, DAT, SLC6A3) is a membrane-spanning protein that pumps the neurotransmitter dopamine out of the synaptic cleft back into cytosol. In the cytosol, other transporters sequester the dopam ...
mediates stimulant and euphoriant effects as well as
psychosis Psychosis is a condition of the mind that results in difficulties determining what is real and what is not real. Symptoms may include delusions and hallucinations, among other features. Additional symptoms are incoherent speech and behavior ...
in high amounts; and activation of the μ-opioid receptor causes analgesic and euphoriant effects. Stimulation of the σ and D2 receptors may also contribute to hallucinogenic and psychotomimetic effects. These are versatile agents with a wide range of possible pharmacological activities depending on the extent and range to which chemical modifications are implemented. The various choice of substitutions that are made allows for "fine-tuning" of the pharmacological profile that results. As examples,
BTCP Benocyclidine, also known as benzothiophenylcyclohexylpiperidine (BTCP), is a psychoactive recreational drug of the arylcyclohexylamine class which is related to phencyclidine (PCP). It was first described in a patent application naming Marc C ...
is a selective
dopamine reuptake inhibitor A dopamine reuptake inhibitor (DRI) is a class of drug which acts as a reuptake inhibitor of the monoamine neurotransmitter dopamine by blocking the action of the dopamine transporter (DAT). Reuptake inhibition is achieved when extracellular dopa ...
, PCP is primarily an NMDA antagonist, and
BDPC BDPC (systematic name 4-(4-bromophenyl)-4-(dimethylamino)-1-(2-phenylethyl)cyclohexanol; also known as bromadol) is a potent narcotic analgesic with a distinctive arylcyclohexylamine chemical structure. It was developed by Daniel Lednicer at Upj ...
is a potent μ-opioid agonist, while
PRE-084 PRE-084 is a sigma receptor agonist, selective for the σ1 subtype. It has nootropic and antidepressant actions in animal studies, as well as antitussive and reinforcing effects. PRE-084 increases the expression of GDNF Glial cell line-deri ...
is a selective
sigma receptor Sigma receptors (σ-receptors) are protein cell surface receptors that bind ligands such as 4-PPBP (4-phenyl-1-(4-phenylbutyl) piperidine), SA 4503 (cutamesine), ditolylguanidine, dimethyltryptamine, and siramesine. There are two subtypes, ...
agonist. Thus, radically different pharmacology is possible through different structural combinations.


Notes on numbering

PCP itself is composed of three six-membered rings, which can each be substituted by a variety of groups. These are traditionally numbered in the older research as first the
cyclohexyl Cyclohexane is a cycloalkane with the molecular formula . Cyclohexane is non-polar. Cyclohexane is a colorless, flammable liquid with a distinctive detergent-like odor, reminiscent of cleaning products (in which it is sometimes used). Cyclohexan ...
ring, then the
phenyl In organic chemistry, the phenyl group, or phenyl ring, is a cyclic group of atoms with the formula C6 H5, and is often represented by the symbol Ph. Phenyl group is closely related to benzene and can be viewed as a benzene ring, minus a hydrogen ...
, and finally the
piperidine Piperidine is an organic compound with the molecular formula (CH2)5NH. This heterocyclic compound, heterocyclic amine consists of a six-membered ring containing five methylene bridges (–CH2–) and one amine bridge (–NH–). It is a colorless ...
ring, with the different rings represented by prime notation (') next to the number. For instance, 4-methyl-PCP, 4'-methyl-PCP and 4''-methyl-PCP are all known compounds, with similar activity but quite different potencies. However, since the widespread sale of these compounds as grey-market designer drugs, nearly all such compounds that have come to prominence either have a bare cyclohexyl ring or a 2-ketocyclohexyl ring, while the piperidine is replaced by a variety of alkyl or cycloalkyl amines and most substitution has taken place on the phenyl ring. Consequently it is common for widely used phenyl substituted analogues such as
3'-MeO-PCP 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 bee ...
and
3'-MeO-PCE 3-Methoxyeticyclidine (3-MeO-PCE), also known as methoxieticyclidine, is a dissociative anesthetic that is qualitatively similar to PCE and PCP and has been sold online as a designer drug. On October 18, 2012 the Advisory Council on the Misuse ...
to be referred to as 3-MeO-PCP and 3-MeO-PCE without the prime, even though this is technically incorrect and could lead to confusion.


List of arylcyclohexylamines


Related compounds

Other similar compounds exist where the base ring has been varied, or the amine chain replaced with other groups. More cycloalkane ring sizes have been experimented with than just purely thinking in terms of the cyclohexylamine. The cyclopentyl homologue of PCP is active with around 1/10th the potency, while the cycloheptyl and cyclooctyl derivatives are inactive, though some substituted arylcycloheptylamines retain activity. The requisite cycloalkylketone is reacted with PhMgBr; 3° alcohol is then reacted with NaN3; azide then reduced with LAH. Then in the final step the piperidine ring is constructed with 1-5-dibromo-pentane. Other compounds are known where the cyclohexyl base ring is replaced by rings such as norbornyl, adamantyl, tetralin, oxane, thiane or piperidine. Conformationally constrained analogs have been prepared and researched by Morieti et al.


References


Further reading

*


External links


Synthesis and Effects of PCP Analogs

Interview with a Ketamine Chemist


{{Monoamine reuptake inhibitors General anesthetics NMDA receptor antagonists Chemical classes of psychoactive drugs