- Source: Osemozotan
Osemozotan (MKC-242) is a selective 5-HT1A receptor agonist with some functional selectivity, acting as a full agonist at presynaptic and a partial agonist at postsynaptic 5-HT1A receptors. 5-HT1A receptor stimulation influences the release of various neurotransmitters including serotonin, dopamine, norepinephrine, and acetylcholine. 5-HT1A receptors are inhibitory G protein-coupled receptor.
Osemozotan has been shown in animal studies to have antidepressant, anxiolytic, antiobsessional, serenic, and analgesic effects. It is used to investigate the role of 5-HT1A receptors in modulating the release of dopamine and serotonin in the brain and their involvement in addiction to stimulants such as cocaine and methamphetamine.
Pharmacodynamics
The binding target of Osemozotan is 5-HT1A receptors. Osemozotan binds with almost 1000 times greater affinity to 5-HT1A receptors than to most other 5-HT, dopamine, or adrenergic receptors. Even with repeated exposure of 5-HT1A receptors to Osemozotan, there is no change in the number of receptors, unlike with other pharmaceutical agonists.
Pharmacokinetics
Pharmacokinetic data collected from animal studies performed in mice and rats revealed an oral tmax of 15 minutes, an area under the curve of 2.943 mg·hr·L−1 and a 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 azapirones 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-HT1A, thus decreasing its specificity and increasing the risk of unwanted effects. Since Osemozotan does not produce this metabolite, it has greater specificity toward 5-HT1A 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-HT1A receptors associated with an inhibitory serotonin-signaling pathway within the spinal cord which causes hypoalgesia and decreasing mechanical allodynia.
= Aggressive behavior
=Osemozotan was found to decrease the incidence of fighting in mice similar to buspirone, diazepam, 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-HT1A 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-HT1A 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 to cocaine may stem from action of the 5-HT1A 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 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.
See also
Piclozotan
Robalzotan
Sarizotan