Osemozotan (MKC-242) is a selective 5-HT_1A receptor

agonist An agonist is a chemical that activates a Receptor (biochemistry), receptor to produce a biological response. Receptors are Cell (biology), cellular proteins whose activation causes the cell to modify what it is currently doing. In contrast, an R ...

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 reference ligand (often the end ...

, 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 agoni ...

at presynaptic and a

partial agonist In pharmacology, partial agonists are drugs that bind to and activate a given Receptor (biochemistry), receptor, but have only partial Intrinsic activity, efficacy at the receptor relative to a full agonist. They may also be considered Ligand (bio ...

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 Chemical synapse, synapse. The cell receiving the signal, or target cell, may be another neuron, but could also be a gland or muscle cell. Neurotra ...

s including

serotonin Serotonin (), also known as 5-hydroxytryptamine (5-HT), is a monoamine neurotransmitter with a wide range of functions in both the central nervous system (CNS) and also peripheral tissues. It is involved in mood, cognition, reward, learning, ...

dopamine Dopamine (DA, a contraction of 3,4-dihydroxyphenethylamine) is a neuromodulatory molecule that plays several important roles in cells. It is an organic chemical of the catecholamine and phenethylamine families. It is an amine synthesized ...

norepinephrine Norepinephrine (NE), also called noradrenaline (NA) or noradrenalin, is an organic compound, organic chemical in the catecholamine family that functions in the brain and human body, body as a hormone, neurotransmitter and neuromodulator. The ...

, and

acetylcholine Acetylcholine (ACh) is an organic compound 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. Par ...

. 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 ...

. Osemozotan has been shown in animal studies to have

antidepressant Antidepressants are a class of medications used to treat major depressive disorder, anxiety disorders, chronic pain, and addiction. Common side effects of antidepressants include Xerostomia, dry mouth, weight gain, dizziness, headaches, akathi ...

anxiolytic An anxiolytic (; also antipanic or anti-anxiety 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 anxie ...

, antiobsessional,

serenic A serenic, or anti-aggressive drug, is a type of drug which reduces the capacity for aggression. Examples Serotonergic agents The recreational drug MDMA ("ecstasy") and a variety of related drugs have been described as '' empathogen-entactogens ...

, and

analgesic An analgesic drug, also called simply an analgesic, antalgic, pain reliever, or painkiller, is any member of the group of drugs used for pain management. Analgesics are conceptually distinct from anesthetics, which temporarily reduce, and in s ...

effects.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. It is used to investigate the role of 5-HT_1A receptors in modulating the release of

and

in the brain and their involvement in addiction to stimulants such as cocaine and

methamphetamine Methamphetamine (contracted from ) is a potent central nervous system (CNS) stimulant that is mainly used as a recreational drug use, recreational or Performance-enhancing substance, performance-enhancing drug and less commonly as a secon ...

Pharmacodynamics

The binding target of Osemozotan is 5-HT_1A receptors. Osemozotan binds with almost 1000 times greater affinity to 5-HT_1A receptors than to most other 5-HT, dopamine, or adrenergic receptors. Even with repeated exposure of 5-HT_1A receptors to Osemozotan, there is no change in the number of receptors, unlike with other

pharmaceutical Medication (also called medicament, medicine, pharmaceutical drug, medicinal product, 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 ...

Pharmacokinetics

Pharmacokinetic data collected from animal studies performed in mice and rats revealed an oral t_max of 15 minutes, an

area under the curve In mathematics, an integral is the continuous analog of a sum, which is used to calculate areas, volumes, and their generalizations. Integration, the process of computing an integral, is one of the two fundamental operations of calculus,Inte ...

of 2.943 mg·hr·L⁻¹ and a

half-life Half-life is a mathematical and scientific description of exponential or gradual decay. Half-life, half life or halflife may also refer to: Film * Half-Life (film), ''Half-Life'' (film), a 2008 independent film by Jennifer Phang * ''Half Life: ...

of 1.3 hours. Pharmacokinetic testing has been able to help explain the longer acting pharmacologic effects of Osemozotan as well as its 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 Augmentation (psychiatry), add-ons to other antidepressants, such as selective serotonin reuptake inhibitors (SSRIs). List of ...

s and requires a substantially lower dose to produce its pharmacologic effects. This result suggests that patients may not have to take the medication as often throughout the day. In these studies, there was a difference in dosage amount required for the intended indication. Osemozotan does not metabolize to 1-(2-pyrimidinyl)-piperazine, a common metabolite found with the azapirone class of medications that has affinity for receptors other than 5-HT_1A, thus decreasing its specificity and increasing the risk of unwanted effects. Since Osemozotan does not produce this metabolite, it has greater specificity toward 5-HT_1A when compared to other anxiolytic medications.

Uses

Osemozotan is being investigated for use in treating pain, aggressive behavior, anxiety, depression, obsessive-compulsive disorder, and dependence on methamphetamine and cocaine.

Pain

It has been proposed that Osemozotan could be used as an analgesic agent because of its activation of 5-HT_1A receptors associated with an inhibitory serotonin-signaling pathway within the spinal cord which causes

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 decreasing mechanical

allodynia Allodynia is a condition in which pain is caused by a stimulus that does not normally elicit pain. For example, sunburn can cause temporary allodynia, so that usually painless stimuli, such as wearing clothing or running cold or warm water over ...

Aggressive behavior

Osemozotan was found to decrease the incidence of fighting in mice similar to

buspirone Buspirone, sold under the brand name Buspar among others, is an anxiolytic, a medication primarily used to treat anxiety disorders, particularly generalized anxiety disorder (GAD). It is a serotonin 5-HT1A receptor, 5-HT1A receptor partial ag ...

diazepam Diazepam, sold under the brand name Valium among others, is a medicine of the benzodiazepine family that acts as an anxiolytic. It is used to treat a range of conditions, including anxiety disorder, anxiety, seizures, alcohol withdrawal syndr ...

, 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 in the mice.

Anxiety and depression

When stimulated, 5-HT_1A receptors are shown to have anxiolytic and antidepressant pharmacologic effects.

Obsessive-compulsive disorder

OCD patients have been found to have increased 5-HT levels in the brain. With the use of Osemozotan as a 5-HT_1A agonist, there is a decrease in serotonergic activity in 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 stimulation, stimulus results in the progressive amplification of a response. Sensitization often is characterized by an enhancement of response to a whole ...

to cocaine may stem from action of the 5-HT_1Areceptor. 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 on 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, particularly in younger adults and in men. Around 60 billion dollars are spent annually for treatments dealing with mental illnesses.

References

{{Serotonergics Benzodioxoles Phenol ethers Chromanes Benzodioxans Secondary amines