Osemozotan (MKC-242) is a selective 5-HT_1A receptor agonist with some functional selectivity, 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 a ...

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 antagonis ...

at postsynaptic 5-HT_1A receptors. 5-HT_1A receptor stimulation influences the release of various neurotransmitters including serotonin, dopamine,

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. 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,

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 anxiet ...

, 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 ...

, and analgesic 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 and serotonin 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 agonists.

Pharmacokinetics

The pharmacokinetic data was collected from animal studies performed in mice and rats. The CMax 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 at ...

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 azapirones 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 1-(2-Pyrimidinyl)piperazine (1-PP, 1-PmP) is a chemical compound and piperazine derivative. It is known to act as an antagonist of the α2-adrenergic receptor (Ki = 7.3–40 nM) and, to a much lesser extent, as a partial agonist of the 5- ...

, 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 ...

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, ...

, and tandospirone 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 sti ...

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.

References

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