Arketamine (developmental code names PCN-101, HR-071603), also known as (''R'')-ketamine or (''R'')-(−)-ketamine, is the (''R'')-(−)
enantiomer of
ketamine.
Similarly to
racemic
In chemistry, a racemic mixture, or racemate (), is one that has equal amounts of left- and right-handed enantiomers of a chiral molecule or salt. Racemic mixtures are rare in nature, but many compounds are produced industrially as racemates. ...
ketamine and
esketamine
Esketamine, also known as (S)-ketamine or S(+)-ketamine, is the ''S''(+) enantiomer of ketamine, is a dissociative hallucinogen drug used as a general anesthetic and as an antidepressant for treatment of depression. It is sold under the brand ...
, the ''S''(+) enantiomer of ketamine, arketamine is
biologically active; however, it is less potent as an
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 ...
and
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 ...
and thus has never been approved or marketed for
clinical use as an
enantiopure
In chemistry, an enantiomer ( /ɪˈnænti.əmər, ɛ-, -oʊ-/ ''ih-NAN-tee-ə-mər''; from Ancient Greek ἐνάντιος ''(enántios)'' 'opposite', and μέρος ''(méros)'' 'part') – also called optical isomer, antipode, or optical anti ...
drug
A drug is any chemical substance that causes a change in an organism's physiology or psychology when consumed. Drugs are typically distinguished from food and substances that provide nutritional support. Consumption of drugs can be via insuffla ...
.
Arketamine is currently in clinical development as a novel
antidepressant
Antidepressants are a class of medication used to treat major depressive disorder, anxiety disorders, chronic pain conditions, and to help manage addictions. Common side-effects of antidepressants include dry mouth, weight gain, dizziness, hea ...
.
Relative to esketamine, arketamine possesses 4 to 5 times lower
affinity
Affinity may refer to:
Commerce, finance and law
* Affinity (law), kinship by marriage
* Affinity analysis, a market research and business management technique
* Affinity Credit Union, a Saskatchewan-based credit union
* Affinity Equity Par ...
for the
PCP site of 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 ...
.
In accordance, arketamine is significantly less potent than racemic ketamine and especially esketamine in terms 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 ...
,
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
sedative-hypnotic
A sedative or tranquilliser is a substance that induces sedation by reducing irritability or excitement. They are CNS depressants and interact with brain activity causing its deceleration. Various kinds of sedatives can be distinguished, but t ...
effects.
Racemic ketamine has weak affinity for the
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, ...
, where it acts as an
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 ...
, whereas esketamine binds negligibly to this receptor, and so the sigma receptor activity of racemic ketamine lies in arketamine.
It was suggested that this action of arketamine may play a role in the
hallucinogenic
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 categorize ...
effects of racemic ketamine and that it may be responsible for the lowering of the
seizure threshold
The term seizure threshold is used to describe the balance between excitatory (glutaminergic) and inhibitory ( GABA-ergic) forces in the brain which affect how susceptible a person is to seizures. Those diagnosed with epilepsy or certain other neur ...
seen with racemic ketamine.
However several subsequent studies have indicated that esketamine is more likely to induce dissociative events, while studies in patients undergoing electroconvulsive therapy suggested that esketamine is a potent inducer of seizures. Esketamine
inhibit
Inhibitor or inhibition may refer to:
In biology
* Enzyme inhibitor, a substance that binds to an enzyme and decreases the enzyme's activity
* Reuptake inhibitor, a substance that increases neurotransmission by blocking the reuptake of a neurotr ...
s 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 ...
about 8-fold more potently than does arketamine, and so is about 8 times more potent as a
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 ...
.
Arketamine and esketamine possess similar potency for interaction with the
muscarinic acetylcholine receptor
Muscarinic acetylcholine receptors, or mAChRs, are acetylcholine receptors that form G protein-coupled receptor complexes in the cell membranes of certain neurons and other cells. They play several roles, including acting as the main end-rece ...
s.
Novel antidepressant
Arketamine appears to be more effective as a rapid-acting antidepressant than esketamine in
preclinical research
In drug development, preclinical development, also termed preclinical studies or nonclinical studies, is a stage of research that begins before clinical trials (testing in humans) and during which important feasibility, iterative testing and drug ...
.
In
rodent studies, esketamine produced
hyperlocomotion,
prepulse inhibition
Prepulse inhibition (PPI) is a neurological phenomenon in which a weaker prestimulus (prepulse) inhibits the reaction of an organism to a subsequent strong reflex-eliciting stimulus (pulse), often using the startle reflex. The stimuli are usually ...
deficits, and
rewarding effects, while arketamine did not, in accordance with its lower potency as an NMDA receptor antagonist and dopamine reuptake inhibitor.
As such, arketamine may have a lower propensity for producing
psychotomimetic A drug with psychotomimetic (also known as psychotogenic) actions mimics the symptoms of psychosis, including delusions and/or delirium, as opposed to only hallucinations. Psychotomimesis is the onset of psychotic symptoms following the administrat ...
effects and a lower
abuse potential
Substance abuse, also known as drug abuse, is the use of a drug in amounts or by methods which are harmful to the individual or others. It is a form of substance-related disorder. Differing definitions of drug abuse are used in public health, ...
in addition to superior antidepressant efficacy.
A study conducted in mice found that ketamine's antidepressant activity is not caused by ketamine inhibiting NMDAR, but rather by sustained activation of a different glutamate receptor, the
AMPA receptor
The α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (also known as AMPA receptor, AMPAR, or quisqualate receptor) is an ionotropic receptor, ionotropic transmembrane receptor for glutamate (iGluR) that mediates fast synapse, synap ...
, by a metabolite, (2R,6R)-
hydroxynorketamine
Hydroxynorketamine (HNK), or 6-hydroxynorketamine, is a minor metabolite of the anesthetic, dissociative, and antidepressant drug ketamine. It is formed by hydroxylation of the intermediate norketamine, another metabolite of ketamine. As of l ...
; as of 2017 it was unknown if this was happening in humans.
Arketamine is an
AMPA receptor agonist
Ampakines, also stylized as AMPAkines, are a subgroup of AMPA receptor positive allosteric modulators with a benzamide or closely related chemical structure. They are also known as "CX compounds". Ampakines take their name from the AMPA receptor ...
.
Paradoxically, arketamine shows greater and longer-lasting rapid
antidepressant
Antidepressants are a class of medication used to treat major depressive disorder, anxiety disorders, chronic pain conditions, and to help manage addictions. Common side-effects of antidepressants include dry mouth, weight gain, dizziness, hea ...
effects in
animal model
An animal model (short for animal disease model) is a living, non-human, often genetic-engineered animal used during the research and investigation of human disease, for the purpose of better understanding the disease process without the risk of ha ...
s of
depression relative to esketamine.
It has been suggested that this may be due to the possibility of different activities of arketamine and esketamine and their respective
metabolite
In biochemistry, a metabolite is an intermediate or end product of metabolism.
The term is usually used for small molecules. Metabolites have various functions, including fuel, structure, signaling, stimulatory and inhibitory effects on enzymes, c ...
s at the
α7-nicotinic receptor, as
norketamine
Norketamine, or ''N''-desmethylketamine, is the major active metabolite of ketamine, which is formed mainly by CYP3A4. Similarly to ketamine, norketamine acts as a noncompetitive NMDA receptor antagonist (Ki = 1.7 μM and 13 μM for (''S'')-(+ ...
and
hydroxynorketamine
Hydroxynorketamine (HNK), or 6-hydroxynorketamine, is a minor metabolite of the anesthetic, dissociative, and antidepressant drug ketamine. It is formed by hydroxylation of the intermediate norketamine, another metabolite of ketamine. As of l ...
are potent
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 ...
s of this receptor and markers of potential rapid antidepressant effects (specifically, increased
mammalian target of rapamycin
The mammalian target of rapamycin (mTOR), also referred to as the mechanistic target of rapamycin, and sometimes called FK506-binding protein 12-rapamycin-associated protein 1 (FRAP1), is a kinase that in humans is encoded by the ''MTOR'' gene. ...
function) correlate closely with their affinity for it.
The picture is unclear however, and other mechanisms have also been implicated.
Clinical development
As of November 2019, arketamine is under development for the treatment of
depression under the developmental code names PCN-101 by Perception Neuroscience in the
United States
The United States of America (U.S.A. or USA), commonly known as the United States (U.S. or US) or America, is a country primarily located in North America. It consists of 50 states, a federal district, five major unincorporated territorie ...
and HR-071603 by Jiangsu Hengrui Medicine in
China
China, officially the People's Republic of China (PRC), is a country in East Asia. It is the world's most populous country, with a population exceeding 1.4 billion, slightly ahead of India. China spans the equivalent of five time zones and ...
.
See also
*
List of investigational antidepressants
This is a list of investigational antidepressants, or antidepressants that are currently under development for clinical use in the treatment of mood disorders but are not yet approved. ''Chemical/generic names are listed first, with developmental ...
References
{{Sigma receptor modulators
Amines
Antidepressants
Arylcyclohexylamines
Dissociative drugs
Dopamine reuptake inhibitors
Enantiopure drugs
Experimental drugs
General anesthetics
Ketones
Muscarinic antagonists
Nicotinic antagonists
NMDA receptor antagonists
Organochlorides
Sedatives
Sigma agonists