Osemozotan (MKC-242) is a
selective 5-HT1A receptor 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 ...
with some
functional selectivity
Functional selectivity (or “agonist trafficking”, “biased agonism”, “biased signaling”, "ligand bias" and “differential engagement”) is the ligand-dependent selectivity for certain signal transduction pathways relative to a referen ...
, acting as a
full 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 ...
at presynaptic and a
partial agonist
In pharmacology, partial agonists are drugs that bind to and activate a given receptor, but have only partial efficacy at the receptor relative to a full agonist. They may also be considered ligands which display both agonistic and antagonistic e ...
at postsynaptic 5-HT
1A receptors.
5-HT
1A receptor stimulation influences the release of various
neurotransmitter
A neurotransmitter is a signaling molecule secreted by a neuron to affect another cell across a synapse. The cell receiving the signal, any main body part or target cell, may be another neuron, but could also be a gland or muscle cell.
Neuro ...
s including
serotonin
Serotonin () or 5-hydroxytryptamine (5-HT) is a monoamine neurotransmitter. Its biological function is complex and multifaceted, modulating mood, cognition, reward, learning, memory, and numerous physiological processes such as vomiting and vas ...
,
dopamine
Dopamine (DA, a contraction of 3,4-dihydroxyphenethylamine) is a neuromodulatory molecule that plays several important roles in cells. It is an organic compound, organic chemical of the catecholamine and phenethylamine families. Dopamine const ...
,
norepinephrine
Norepinephrine (NE), also called noradrenaline (NA) or noradrenalin, is an organic chemical in the catecholamine family that functions in the brain and body as both a hormone and neurotransmitter. The name "noradrenaline" (from Latin '' ad'', ...
, and
acetylcholine
Acetylcholine (ACh) is an organic chemical that functions in the brain and body of many types of animals (including humans) as a neurotransmitter. Its name is derived from its chemical structure: it is an ester of acetic acid and choline. Part ...
.
5-HT
1A receptors are inhibitory
G protein-coupled receptor
G protein-coupled receptors (GPCRs), also known as seven-(pass)-transmembrane domain receptors, 7TM receptors, heptahelical receptors, serpentine receptors, and G protein-linked receptors (GPLR), form a large group of evolutionarily-related p ...
.
Osemozotan has
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 ...
,
anxiolytic
An anxiolytic (; also antipanic or antianxiety agent) is a medication or other intervention that reduces anxiety. This effect is in contrast to anxiogenic agents which increase anxiety. Anxiolytic medications are used for the treatment of anxi ...
,
antiobsessional,
serenic A serenic, or antiaggressive agent, is a type of drug which reduces the capacity for irritability and aggression.
Examples
The recreational drug MDMA ("ecstasy") and a variety of related drugs have been described as ''empathogen-entactogens'', or s ...
, and
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 ...
effects in animal studies,
[Abe, Michikazu, Hiroshi Nakai, Reiko Tabata, Ken-Ichi Saito, and Mitsuo Egawa. "Effect of 5--1,3-benzodioxole HCL (MKC-242), a Novel 5-HT1A-Receptor Agonist, on Aggressive Behavior and Marble Burying Behavior in Mice." ''Jpn. J. Pharmacol.'' 76 (1998): 297-304.] and is used to investigate the role of 5-HT
1A receptors in modulating the release of
dopamine
Dopamine (DA, a contraction of 3,4-dihydroxyphenethylamine) is a neuromodulatory molecule that plays several important roles in cells. It is an organic compound, organic chemical of the catecholamine and phenethylamine families. Dopamine const ...
and
serotonin
Serotonin () or 5-hydroxytryptamine (5-HT) is a monoamine neurotransmitter. Its biological function is complex and multifaceted, modulating mood, cognition, reward, learning, memory, and numerous physiological processes such as vomiting and vas ...
in the brain, and their involvement in addiction to abused stimulants such as cocaine and methamphetamine.
Pharmacodynamics
The target of Osemozotan is 5-HT
1A receptors. This molecules bind with almost 1000 times greater affinity to 5-HT
1A receptors than most other 5-HT, dopamine, or adrenergic receptors.
With repeated exposure of Osemozotan at the 5-HT
1A receptors, there seems to be no change in the number of receptors, which is not typically seen with pharmaceutical
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 ...
s.
Pharmacokinetics
The pharmacokinetic data was collected from animal studies performed in mice and rats. The
CMax
CMAX is a bus rapid transit (BRT) service in Central Ohio, operated by the Central Ohio Transit Authority (COTA). The line begins in Downtown Columbus, traveling northeast to Westerville. CMAX is Central Ohio's first bus rapid transit line; it ...
was obtained 15 minutes after oral ingestion of Osemozotan, the
area under the curve
In mathematics, an integral assigns numbers to functions in a way that describes displacement, area, volume, and other concepts that arise by combining infinitesimal data. The process of finding integrals is called integration. Along with ...
was 2,943 ng x hr/mL and the
half-life
Half-life (symbol ) is the time required for a quantity (of substance) to reduce to half of its initial value. The term is commonly used in nuclear physics to describe how quickly unstable atoms undergo radioactive decay or how long stable ato ...
was 1.3 hours.
The pharmacokinetic testing has been able to help explain the longer acting pharmacologic effects of Osemozotan, and the increased potency. Osemozotan was shown to have increased duration of pharmacologic effects compared to
azapirone
Azapirones are a class of drugs used as anxiolytics, antidepressants, and antipsychotics. They are commonly used as add-ons to other antidepressants, such as selective serotonin reuptake inhibitors (SSRIs).
Medical uses
Azapirones have shown ...
s and requires a substantially lower dose to produce its pharmacologic effects.
This may be attractive to populations that will have to take this medication in that they may not have to take the medication as often throughout the day. In these studies there was a difference in dosage amount necessary for the indication it is used.
Osemozotan has not been found to be metabolized to
1-(2-pyrimidinyl)-piperazine, a common metabolite found with the azapirone class of medications.
1-(2-pyrimidinyl)-piperazine has affinity for receptors other than 5-HT
1A, decreasing its specificity and increasing the risk of unwanted effects.
Since Osemozotan does not express this metabolite, it has greater specificity to 5-HT
1A compared to other anxiolytic medications.
Uses
As mentioned above, Osemozotan is being investigated in its usage to treat pain, aggressive behavior, anxiety, depression,
obsessive-compulsive disorder, and drug dependence with methamphetamine and cocaine.
Pain
It has been proposed that Osemozotan be used as an analgesic agent because of its activation of 5-HT
1A receptors that lead to inhibitory serotonin signaling pathway within the spinal cord to cause
hypoalgesia
Hypoalgesia or hypalgesia denotes a decreased sensitivity to painful stimuli.
Hypoalgesia occurs when nociceptive (painful) stimuli are interrupted or decreased somewhere along the path between the input (nociceptors), and the places where they a ...
and decrease mechanical
allodynia
Allodynia is a condition in which pain is caused by a stimulus that does not normally elicit pain. For example, bad sunburn can cause temporary allodynia, and touching sunburned skin, or running cold or warm water over it, can be very painful. It i ...
.
Aggressive behavior
Osemozotan was found to decrease the number of fighting incidences in mice similar to
buspirone
Buspirone, sold under the brand name Buspar, among others, is a medication primarily used to treat anxiety disorders, particularly generalized anxiety disorder. Benefits support its short-term use. It is taken by mouth, and it may take up to fo ...
,
diazepam
Diazepam, first marketed as Valium, is a medicine of the benzodiazepine family that acts as an anxiolytic. It is commonly used to treat a range of conditions, including anxiety, seizures, alcohol withdrawal syndrome, muscle spasms, insomnia, a ...
, and
tandospirone
Tandospirone (brand name Sediel) is an anxiolytic and antidepressant drug used in China and Japan, where it is marketed by Dainippon Sumitomo Pharma. It is a member of the azapirone class of drugs and is closely related to other azapirones l ...
but required a lower pharmacologic dose to produce beneficial effects.
Osemozotan showed dose-dependent anti-aggressive effects and was not shown to decrease motor coordination within the mice.
Anxiety and depression
5-HT
1A receptors when stimulated have shown to have anxiolytic and antidepressant pharmacologic effects.
Obsessive-Compulsive Disorder (OCD)
Obsessive-Compulsive patients have been found to have increased 5-HT levels within the brain.
With the use of Osemozotan as a 5-HT
1A agonist, there will be a decrease in serotonergic activity within the brain, leading to possible anti-obsessional pharmacological action.
One animal mouse model used to test for OCD is known as the marble burying test in which the amount of marbles buried within a certain time frame is recorded.
Mice performed the marble burying test both with and without Osemozotan. With Osemozotan administration, the number of marbles buried was decreased with apparently little to no loss in motor coordination; these test results support the theory that Osemozotan may be useful in the treatment of OCD.
Drug dependence
It has been noted that
sensitization
Sensitization is a non-associative learning process in which repeated administration of a stimulus results in the progressive amplification of a response. Sensitization often is characterized by an enhancement of response to a whole class of stim ...
of cocaine may stem from action of the 5-HT
1A receptor.
While the role of 5-HT receptors with methamphetamine is still not certain, the use of osemozotan was found to decrease 5-HT levels in patients with repeated methamphetamine exposure; this may be a possibility for treatment of drug dependence with cocaine and methamphetamine.
Prevalence of mental disease states
About 18% of American adults suffer from some type of anxiety disorder and 1 in 5 adults in the United States are on some type of medication to help control or improve their behavior.
The prevalence of prescription medication use for mental illnesses has noticeably increased in the past few years, with increasing numbers in the younger adults and in men.
Around 60 billion dollars are spent annually for treatments dealing with mental illnesses.
See also
*
Piclozotan
Piclozotan (SUN-N4057) is a selective 5-HT1A receptor partial agonist, which has neuroprotective effects in animal studies. It has been through early clinical trials in humans for treatment of acute stroke, but results have not yet been announ ...
*
Robalzotan
Robalzotan (NAD-299, AZD-7371) is a selective antagonist at the 5-HT1A receptor. It was shown to completely reverse the autoreceptor-mediated inhibition of serotonin release induced by the administration of selective serotonin reuptake inhibito ...
*
Sarizotan
References
{{Serotonergics
Benzodioxoles
Phenol ethers
Chromanes