2-Fluorodeschloroketamine (also known as 2'-Fl-2-Oxo-PCM, Fluoroketamine and 2-FDCK) is a

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 ...

anesthetic An anesthetic (American English) or anaesthetic (British English; see spelling differences) is a drug used to induce anesthesia ⁠— ⁠in other words, to result in a temporary loss of sensation or awareness. They may be divided into two ...

related to

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 ...

. Its sale and use as a

designer drug A designer drug is a structural or functional analog of a controlled substance that has been designed to mimic the pharmacological effects of the original drug, while avoiding classification as illegal and/or detection in standard drug tests. Des ...

has been reported in various countries. It is an analogue of ketamine where the

chlorine Chlorine is a chemical element with the Symbol (chemistry), symbol Cl and atomic number 17. The second-lightest of the halogens, it appears between fluorine and bromine in the periodic table and its properties are mostly intermediate betwee ...

group has been replaced by

fluorine Fluorine is a chemical element with the symbol F and atomic number 9. It is the lightest halogen and exists at standard conditions as a highly toxic, pale yellow diatomic gas. As the most electronegative reactive element, it is extremely reacti ...

. Due to its recent emergence, the pharmacological specifics of the compound are mostly unclear. Effects are still ketamine like but with more euphoria and analgesic properties.

History

The synthesis of 2-FDCK was first described in a 2013 paper as part of a larger effort to synthesize and evaluate new anesthetic drugs based on ketamine and its analogues. Ketamine itself was first introduced in 1964 and was approved for clinical use in 1970. Since then it has become one of the most important and applicable general anesthetics as well as a popular recreational drug. The use of 2-FDCK as a research chemical has been reported in various countries.European Monitoring Centre for Drugs and Drug Addiction (2017), EMCDDA–Europol 2016 Annual Report on the implementation of Council Decision 2005/387/JHA, Implementation reports, Publications Office of the European Union, Luxembourg. Many of these new psychoactive substances (

NPS NPS may refer to: Organizations * National Park Service, U.S. * National Pension System, India * National Pension Service, Korea * National Phobics Society, UK charity * National Piers Society, UK charity * National Poetry Slam, competition * N ...

) appear on the drug market in order to circumvent existing drug policies. 2-FDCK was first formally notified by the

EMCDDA The European Monitoring Centre for Drugs and Drug Addiction (EMCDDA) is an agency of the European Union located in Lisbon, Portugal, and established in 1993. In June 2022, the Council of the European Union approved a reform of the organization ...

in 2016, alongside 65 other new substances. Due to its recent appearance, little research has been done on the compound so far.

Chemistry

Structure

The full chemical name of 2-FDCK is 2-(2-fluorophenyl)-2-(methylamino)cyclohexan-1-one. Synthesis_of_2-FDCK

2-FDCK belongs to a class of compounds called

arylcyclohexylamine Arylcyclohexylamines, also known as arylcyclohexamines or arylcyclohexanamines, are a chemical class of pharmaceutical, designer, and experimental drugs. History Phencyclidine (PCP) is believed to be the first arylcyclohexylamine with recogniz ...

s which contains various other drugs such as PCP and

. Their general structure consists 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 ...

group attached to the same carbon as 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 ...

. 2-FDCK has an o-fluorophenyl group as an aryl substituent and the amine group is methylated. The cyclohexyl ring features a

ketone In organic chemistry, a ketone is a functional group with the structure R–C(=O)–R', where R and R' can be a variety of carbon-containing substituents. Ketones contain a carbonyl group –C(=O)– (which contains a carbon-oxygen double bo ...

group next to the amine position. The chemical structure of 2-FDCK differs from ketamine only in that there is a fluorine atom attached to the phenyl group. Ketamine has a chlorine atom in that position.

Synthesis

2-FDCK can be synthesized in a five-step reaction process. First 2-fluorobenzonitrile reacts with the

Grignard reagent A Grignard reagent or Grignard compound is a chemical compound with the general formula , where X is a halogen and R is an organic group, normally an alkyl or aryl. Two typical examples are methylmagnesium chloride and phenylmagnesium bromide ...

cyclopentyl magnesium bromide followed by a

bromination In chemistry, halogenation is a chemical reaction that entails the introduction of one or more halogens into a compound. Halide-containing compounds are pervasive, making this type of transformation important, e.g. in the production of polymers, ...

reaction to obtain α-bromocyclopentyl-(2-fluorophenyl)-ketone. The reaction of the obtained ketone with methylamine at -40 °C then results in the formation of α-hydroxycyclopentyl-(2-fluorophenyl)-N-methylamine. Finally, the five-membered ring cyclopentanol form is expanded to a cyclohexylketone form by a thermal rearrangement reaction.

HCl HCL may refer to: Science and medicine * Hairy cell leukemia, an uncommon and slowly progressing B cell leukemia * Harvard Cyclotron Laboratory, from 1961 to 2002, a proton accelerator used for research and development * Hollow-cathode lamp, a spe ...

is used to create a water-soluble HCl salt of 2-FDCK.

Detection

2-FDCK and its metabolites can be detected in

urine Urine is a liquid by-product of metabolism in humans and in many other animals. Urine flows from the kidneys through the ureters to the urinary bladder. Urination results in urine being excretion, excreted from the body through the urethra. Cel ...

with the use of liquid chromatography mass spectrometry ( LC/MS).

Pharmacology

Metabolism

The metabolism of 2-FDCK is analogous to that of ketamine: the enzymes

CYP2B6 Cytochrome P450 2B6 is an enzyme that in humans is encoded by the ''CYP2B6'' gene. CYP2B6 is a member of the cytochrome P450 group of enzymes. Along with CYP2A6, it is involved with metabolizing nicotine, along with many other substances. Funct ...

and

CYP3A4 Cytochrome P450 3A4 (abbreviated CYP3A4) () is an important enzyme in the body, mainly found in the liver and in the intestine. It oxidizes small foreign organic molecules (xenobiotics), such as toxins or drugs, so that they can be removed from t ...

, the latter to a lesser extent, metabolise 2-FDCK to Nor-2FDCK via

N-demethylation Demethylation is the chemical process resulting in the removal of a methyl group (CH3) from a molecule. A common way of demethylation is the replacement of a methyl group by a hydrogen atom, resulting in a net loss of one carbon and two hydrogen ato ...

. This is further metabolised either to dehydronor-2FDCK by CYP2B6 or to hydroxynor-2FDCK by CYP2A6 and CYP2B6. In general, the 2-FDCK equivalent shows stronger docking to CYP2B6 in simulations, as well as slower metabolism rate, than the more well-known ketamine. The

lipophilicity Lipophilicity (from Greek λίπος "fat" and φίλος "friendly"), refers to the ability of a chemical compound to dissolve in fats, oils, lipids, and non-polar solvents such as hexane or toluene. Such non-polar solvents are themselves lipop ...

is observed to be lower for 2-FDCK than for ketamine.

In vitro to in vivo extrapolation In vitro to in vivo extrapolation (IVIVE) refers to the qualitative or quantitative transposition of experimental results or observations made in vitro to predict phenomena in vivo, biological organisms. The problem of transposing in vitro results ...

predicts that in the body, 2-FDCK shows a lower intrinsic hepatic clearance than ketamine. Both of these characteristics would suggest that the effects of 2-FDCK last longer than those of ketamine.

Pharmacodynamics

2-FDCK is structurally similar to ketamine, so a similar mechanism of action is expected, but there has been no study done to confirm this. Due to the halogen in the 2 position not being a chlorine but a fluorine, the molecule is less polar. This could influence binding to proteins, such as the

NMDA receptor The ''N''-methyl-D-aspartate receptor (also known as the NMDA receptor or NMDAR), is a glutamate receptor and ion channel found in neurons. The NMDA receptor is one of three types of ionotropic glutamate receptors, the other two being AMPA rece ...

that ketamine primarily binds to and acts as an

antagonist An antagonist is a character in a story who is presented as the chief foe of the protagonist. Etymology The English word antagonist comes from the Greek ἀνταγωνιστής – ''antagonistēs'', "opponent, competitor, villain, enemy, riv ...

towards.

Comparison to other halogen-substituted ketamine variants

For general (halogen) substitutions of ketamine, docking strength for CYP2B6 follows the pattern H < Br < Cl < F. The parameter of internal clearance follows the pattern Br > Cl > F > H. Lastly, K_m (

Michaelis constant Michaelis or Michelis is a surname. Notable people and characters with the surname include: * Adolf Michaelis, German classical scholar * Anthony R. Michaelis, German science writer * Edward Michelis, German theologian * Georg Michaelis, German p ...

) follows the pattern of Br < Cl < F < H, and as such the in-vitro metabolism rate follows the inverse pattern, namely Br > Cl > F > H.

Effects

Dosage

2-FDCK is very new and not yet sufficiently studied. Therefore, information on dosage can only be obtained from purely anecdotal sources.

Possible effects and dangers

In 2019, 2-FDCK was found in poisoned individuals in Hong Kong in combination with other ketamine-type drugs. 2-FDCK was not assumed to be an impurity because it was present in high levels while ketamine was present at trace levels. The actual drug specimens were not available, so it was not possible to verify this. Clinical effects were observed but because the drug was taken in combination with other ones, it was not possible to determine what effects were caused by which drug. The clinically observed effects of the patients were: impaired consciousness, agitation, abnormal behaviour,

hypertension Hypertension (HTN or HT), also known as high blood pressure (HBP), is a long-term medical condition in which the blood pressure in the arteries is persistently elevated. High blood pressure usually does not cause symptoms. Long-term high bl ...

and

tachycardia Tachycardia, also called tachyarrhythmia, is a heart rate that exceeds the normal resting rate. In general, a resting heart rate over 100 beats per minute is accepted as tachycardia in adults. Heart rates above the resting rate may be normal (su ...

. Most patients were discharged from the hospital after a few days of supportive treatment.

Legal status

Due to the fast emergence of NPS, new substances such as 2-FDCK are often not yet specifically mentioned in

controlled substance A controlled substance is generally a drug or chemical whose manufacture, possession and use is regulated by a government, such as illicitly used drugs or prescription medications that are designated by law. Some treaties, notably the Single C ...

legislation. As a result, NPS are sometimes marketed as ' legal highs'. 2-FDCK is currently illegal in Italy Japan, Latvia, Singapore, Sweden, Switzerland, as well as being covered by blanket bans in Canada, Belgium, and the UK.

References

__FORCETOC__ {{DEFAULTSORT:Fluorodeschloroketamine, 2- Arylcyclohexylamines Designer drugs Dissociative drugs Fluoroarenes Ketones NMDA receptor antagonists