Osemozotan

Last updated
Osemozotan
Osemozotan.svg
Legal status
Legal status
  • In general: uncontrolled
Identifiers
  • 5-(3-[((2S)-1,4-benzodioxan-2-ylmethyl)amino]propoxy)-1,3-benzodioxole
CAS Number
PubChem CID
ChemSpider
UNII
CompTox Dashboard (EPA)
Chemical and physical data
Formula C19H21NO5
Molar mass 343.379 g·mol−1
3D model (JSmol)
  • C1[C@@H](OC2=CC=CC=C2O1)CNCCCOC3=CC4=C(C=C3)OCO4
  • InChI=1S/C19H21NO5/c1-2-5-18-16(4-1)22-12-15(25-18)11-20-8-3-9-21-14-6-7-17-19(10-14)24-13-23-17/h1-2,4-7,10,15,20H,3,8-9,11-13H2/t15-/m0/s1 X mark.svgN
  • Key:MEEQBDCQPIZMLY-HNNXBMFYSA-N X mark.svgN
 X mark.svgNYes check.svgY  (what is this?)    (verify)

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. [1] 5-HT1A receptor stimulation influences the release of various neurotransmitters including serotonin, dopamine, norepinephrine, and acetylcholine. [2] 5-HT1A receptors are inhibitory G protein-coupled receptor. [3]

Contents

Osemozotan has been shown in animal studies to have antidepressant, anxiolytic, antiobsessional, serenic, and analgesic effects. [4] [5] [6] [2] It is used to investigate the role of 5-HT1A receptors in modulating the release of dopamine and serotonin in the brain [7] [8] and their involvement in addiction to stimulants such as cocaine and methamphetamine. [9] [10] [11] [12] [13]

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. [2] Even with repeated exposure of 5-HT1A receptors to Osemozotan, there is no change in the number of receptors, unlike with other pharmaceutical agonists. [14]

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. [6] 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. [6] 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. [6] 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. [6] 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. [2] [6]

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. [2] [15]

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. [6] Osemozotan showed dose-dependent anti-aggressive effects and was not shown to decrease motor coordination in the mice. [6]

Anxiety and depression

When stimulated, 5-HT1A receptors are shown to have anxiolytic and antidepressant pharmacologic effects. [2]

Obsessive-compulsive disorder

OCD patients have been found to have increased 5-HT levels in the brain. [1] [16] 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. [6] 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. [6] 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. [6]

Drug dependence

It has been noted that sensitization to cocaine may stem from action of the 5-HT1A receptor. [10] [17] 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. [9]

Prevalence of mental disease states

About 18% of American adults suffer from some type of anxiety disorder, [18] and 1 in 5 adults in the United States are on some type of medication to help control or improve their behavior. [19] The prevalence of prescription medication use for mental illnesses has noticeably increased in the past few years,[ when? ] particularly in younger adults and in men. [19] Around 60 billion dollars are spent annually for treatments dealing with mental illnesses. [20]

See also

Related Research Articles

<span class="mw-page-title-main">Empathogen</span> Class of psychoactive drugs that produce empathic experiences

Empathogens or entactogens are a class of psychoactive drugs that induce the production of experiences of emotional communion, oneness, relatedness, emotional openness—that is, empathy or sympathy—as particularly observed and reported for experiences with 3,4-methylenedioxymethamphetamine (MDMA). This class of drug is distinguished from the classes of hallucinogen or psychedelic, and amphetamine or stimulants. Major members of this class include MDMA, MDA, MDEA, MDOH, MBDB, 5-APB, 5-MAPB, 6-APB, 6-MAPB, methylone, mephedrone, GHB, αMT, and αET, MDAI among others. Most entactogens are phenethylamines and amphetamines, although several, such as αMT and αET, are tryptamines. When referring to MDMA and its counterparts, the term MDxx is often used. Entactogens are sometimes incorrectly referred to as hallucinogens or stimulants, although many entactogens such as ecstasy exhibit psychedelic or stimulant properties as well.

<span class="mw-page-title-main">5-HT receptor</span> Class of transmembrane proteins

5-HT receptors, 5-hydroxytryptamine receptors, or serotonin receptors, are a group of G protein-coupled receptor and ligand-gated ion channels found in the central and peripheral nervous systems. They mediate both excitatory and inhibitory neurotransmission. The serotonin receptors are activated by the neurotransmitter serotonin, which acts as their natural ligand.

<span class="mw-page-title-main">Azapirone</span> Drug class of psycotropic drugs

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).

<span class="mw-page-title-main">Pindolol</span> Chemical compound

Pindolol, sold under the brand name Visken among others, is a nonselective beta blocker which is used in the treatment of hypertension. It is also an antagonist of the serotonin 5-HT1A receptor, preferentially blocking inhibitory 5-HT1A autoreceptors, and has been researched as an add-on therapy to various antidepressants, such as clomipramine and the selective serotonin reuptake inhibitors (SSRIs), in the treatment of depression and obsessive-compulsive disorder.

<span class="mw-page-title-main">Serotonin receptor agonist</span> Neurotransmission-modulating substance

A serotonin receptor agonist is an agonist of one or more serotonin receptors. They activate serotonin receptors in a manner similar to that of serotonin, a neurotransmitter and hormone and the endogenous ligand of the serotonin receptors.

5-HT<sub>1A</sub> receptor Serotonin receptor protein distributed in the cerebrum and raphe nucleus

The serotonin 1A receptor is a subtype of serotonin receptors, or 5-HT receptors, that binds serotonin, also known as 5-HT, a neurotransmitter. 5-HT1A is expressed in the brain, spleen, and neonatal kidney. It is a G protein-coupled receptor (GPCR), coupled to the Gi protein, and its activation in the brain mediates hyperpolarization and reduction of firing rate of the postsynaptic neuron. In humans, the serotonin 1A receptor is encoded by the HTR1A gene.

<span class="mw-page-title-main">8-OH-DPAT</span> Chemical compound

8-OH-DPAT is a research chemical of the aminotetralin chemical class which was developed in the 1980s and has been widely used to study the function of the 5-HT1A receptor. It was one of the first major 5-HT1A receptor full agonists to have been discovered.

<span class="mw-page-title-main">WAY-100635</span> Chemical compound

WAY-100635 is a piperazine drug and research chemical widely used in scientific studies. It was originally believed to act as a selective 5-HT1A receptor antagonist, but subsequent research showed that it also acts as potent full agonist at the D4 receptor. It is sometimes referred to as a silent antagonist at the former receptor. It is closely related to WAY-100135.

<span class="mw-page-title-main">Flesinoxan</span> Chemical compound

Flesinoxan (DU-29,373) is a potent and selective 5-HT1A receptor partial/near-full agonist of the phenylpiperazine class. Originally developed as a potential antihypertensive drug, flesinoxan was later found to possess antidepressant and anxiolytic effects in animal tests. As a result, it was investigated in several small human pilot studies for the treatment of major depressive disorder, and was found to have robust effectiveness and very good tolerability. However, due to "management decisions", the development of flesinoxan was stopped and it was not pursued any further.

<span class="mw-page-title-main">MTEP</span> Chemical compound

3-( ethynyl)pyridine (MTEP) is a research drug that was developed by Merck & Co. as a selective allosteric antagonist of the metabotropic glutamate receptor subtype mGluR5. Identified through structure-activity relationship studies on an older mGluR5 antagonist MPEP, MTEP has subsequently itself acted as a lead compound for newer and even more improved drugs.

<span class="mw-page-title-main">RS-102221</span> Chemical compound

RS-102221 is a drug developed by Hoffmann–La Roche, which was one of the first compounds discovered that acts as a potent and selective antagonist at the serotonin 5-HT2C receptor, with around 100× selectivity over the closely related 5-HT2A and 5-HT2B receptors. It has anxiolytic effects in animal studies, increases the effectiveness of SSRI antidepressants, and shows a complex interaction with cocaine, increasing some effects but decreasing others, reflecting a role for the 5-HT2C receptor in regulation of the dopamine signalling system in the brain.

<span class="mw-page-title-main">CP-94253</span> Potent and selective serotonin 5-HT1B receptor agonist

CP-94253 is a drug which acts as a potent and selective serotonin 5-HT1B receptor agonist, with approximately 25× and 40× selectivity over the closely related 5-HT1D and 5-HT1A receptors. It has a range of behavioral effects, based on animal testing. The effects include the following: promoting wakefulness by increasing dopamine release in the brain; reducing food intake and promoting satiety; enhancing the reinforcing effects of cocaine; and possible antidepressant effects. A recent study found that "Regardless of sex, CP94253 decreased cocaine intake after abstinence and during resumption of SA [self-administration] and decreased cue reactivity" suggesting that agonism of the inhibitory 5-HT2B receptors may diminish the cognitive reward of cocaine usage and increased use of the drug without a period of abstinence may be a product of test subjects trying to achieve a previously rewarding experience through larger dosages of cocaine.

<span class="mw-page-title-main">RU-24,969</span> Chemical compound

RU-24,969 is a serotonergic drug used in scientific research. It is a selective agonist of the serotonin 5-HT1A and 5-HT1B receptors, with 5-fold preference for the latter receptor over the former. It also has affinity for the serotonin 5-HT5A, 5-HT5B, and 5-HT7 receptors.

<span class="mw-page-title-main">S-15535</span> Chemical compound

S-15535 is a phenylpiperazine drug which is a potent and highly selective 5-HT1A receptor ligand that acts as an agonist and antagonist at the presynaptic and postsynaptic 5-HT1A receptors, respectively. It has anxiolytic properties.

<span class="mw-page-title-main">GR-127935</span> Drug

GR-127935 is a drug which acts as a selective antagonist at the serotonin receptors 5-HT1B and 5-HT1D. It has little effect when given by itself but blocks the antiaggressive effect of 5-HT1B agonists, and alters release of serotonin in the brain, as well as reducing drug-seeking behaviour in cocaine addicted rats.

<span class="mw-page-title-main">Serotonin antagonist and reuptake inhibitor</span> Class of drug

Serotonin antagonist and reuptake inhibitors (SARIs) are a class of drugs used mainly as antidepressants, but also as anxiolytics and hypnotics. They act by antagonizing serotonin receptors such as 5-HT2A and inhibiting the reuptake of serotonin, norepinephrine, and/or dopamine. Additionally, most also antagonize α1-adrenergic receptors. The majority of the currently marketed SARIs belong to the phenylpiperazine class of compounds.

<span class="mw-page-title-main">Adatanserin</span> Chemical compound

Adatanserin is a mixed 5-HT1A receptor partial agonist and 5-HT2A and 5-HT2C receptor antagonist. It was under development by Wyeth as an antidepressant but was ultimately not pursued.

<span class="mw-page-title-main">F-15,599</span> Chemical compound

F-15,599, also known as NLX-101, is a potent and selective 5-HT1A receptor full agonist. In addition, it displays functional selectivity, or biased agonism, by preferentially activating postsynaptic serotonin 5-HT1A receptors over somatodendritic serotonin 5-HT1A autoreceptors. The drug has been investigated for potential use as a pharmaceutical drug in the treatment of conditions including depression, schizophrenia, cognitive disorders, Rett syndrome, and fragile X syndrome.

<span class="mw-page-title-main">Indorenate</span> Chemical compound

Indorenate (TR-3369), is a tryptamine derivative which acts as an agonist at the 5-HT1A, 5-HT1B and 5-HT2C serotonin receptors. It has anxiolytic, antihypertensive and anorectic effects, predominantly through action at 5-HT1A, but with some contribution from the 5-HT1B and 5-HT2C subtypes, and possibly some other non-serotonergic targets also.

<span class="mw-page-title-main">SB-206553</span> Chemical compound

SB-206553 is a drug which acts as a mixed antagonist for the 5-HT2B and 5-HT2C serotonin receptors. It has anxiolytic properties in animal studies and interacts with a range of other drugs. It has also been shown to act as a positive allosteric modulator of α7 nicotinic acetylcholine receptors. Modified derivatives of SB-206553 have been used to probe the structure of the 5-HT2B receptor.

References

  1. 1 2 Matsuda T, Yoshikawa T, Suzuki M, Asano S, Somboonthum P, Takuma K, et al. (December 1995). "Novel benzodioxan derivative, 5-(3-[((2S)-1,4-benzodioxan-2- ylmethyl)amino]propoxy)-1,3-benzodioxole HCl (MKC-242), with a highly potent and selective agonist activity at rat central serotonin1A receptors". Japanese Journal of Pharmacology. 69 (4): 357–66. doi: 10.1254/jjp.69.357 . PMID   8786639.
  2. 1 2 3 4 5 6 Matsuda T (2013). "Neuropharmacologic studies on the brain serotonin1A receptor using the selective agonist osemozotan". Biological & Pharmaceutical Bulletin. 36 (12): 1871–82. doi: 10.1248/bpb.b13-00645 . PMID   24292048.
  3. ↑ Saudou F, Hen R (December 1994). "5-Hydroxytryptamine receptor subtypes in vertebrates and invertebrates". Neurochemistry International. 25 (6): 503–32. doi:10.1016/0197-0186(94)90150-3. PMID   7894328. S2CID   34436470.
  4. ↑ Abe M, Tabata R, Saito K, Matsuda T, Baba A, Egawa M (August 1996). "Novel benzodioxan derivative, 5-[3-[((2S)-1,4-benzodioxan-2-ylmethyl) amino]propoxy]-1,3-benzodioxole HCl (MKC-242), with anxiolytic-like and antidepressant-like effects in animal models". The Journal of Pharmacology and Experimental Therapeutics. 278 (2): 898–905. PMID   8768745.
  5. ↑ Sakaue M, Ago Y, Sowa C, Koyama Y, Baba A, Matsuda T (January 2003). "The 5-HT1A receptor agonist MKC-242 increases the exploratory activity of mice in the elevated plus-maze". European Journal of Pharmacology. 458 (1–2): 141–4. doi:10.1016/S0014-2999(02)02786-3. PMID   12498918.
  6. 1 2 3 4 5 6 7 8 9 10 11 Abe, Michikazu, Hiroshi Nakai, Reiko Tabata, Ken-Ichi Saito, and Mitsuo Egawa. "Effect of 5-{3-[((2S)-1,4-Benzodioxan-2-ylmethyl)amino]propoxy}-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.
  7. ↑ Sakaue M, Somboonthum P, Nishihara B, Koyama Y, Hashimoto H, Baba A, Matsuda T (March 2000). "Postsynaptic 5-hydroxytryptamine(1A) receptor activation increases in vivo dopamine release in rat prefrontal cortex". British Journal of Pharmacology. 129 (5): 1028–34. doi:10.1038/sj.bjp.0703139. PMC   1571922 . PMID   10696105.
  8. ↑ Ago Y, Koyama Y, Baba A, Matsuda T (December 2003). "Regulation by 5-HT1A receptors of the in vivo release of 5-HT and DA in mouse frontal cortex". Neuropharmacology. 45 (8): 1050–6. doi:10.1016/S0028-3908(03)00304-6. PMID   14614948. S2CID   20463997.
  9. 1 2 Ago Y, Nakamura S, Uda M, Kajii Y, Abe M, Baba A, Matsuda T (September 2006). "Attenuation by the 5-HT1A receptor agonist osemozotan of the behavioral effects of single and repeated methamphetamine in mice". Neuropharmacology. 51 (4): 914–22. doi:10.1016/j.neuropharm.2006.06.001. PMID   16863654. S2CID   38888234.
  10. 1 2 Ago Y, Nakamura S, Hayashi A, Itoh S, Baba A, Matsuda T (September 2006). "Effects of osemozotan, ritanserin and azasetron on cocaine-induced behavioral sensitization in mice". Pharmacology, Biochemistry, and Behavior. 85 (1): 198–205. doi:10.1016/j.pbb.2006.07.036. PMID   16962650. S2CID   1794862.
  11. ↑ Ago Y, Nakamura S, Baba A, Matsuda T (January 2008). "Neuropsychotoxicity of abused drugs: effects of serotonin receptor ligands on methamphetamine- and cocaine-induced behavioral sensitization in mice". Journal of Pharmacological Sciences. 106 (1): 15–21. doi: 10.1254/jphs.FM0070121 . PMID   18198473.
  12. ↑ Tsuchida R, Kubo M, Kuroda M, Shibasaki Y, Shintani N, Abe M, et al. (March 2009). "An antihyperkinetic action by the serotonin 1A-receptor agonist osemozotan co-administered with psychostimulants or the non-stimulant atomoxetine in mice". Journal of Pharmacological Sciences. 109 (3): 396–402. doi: 10.1254/jphs.08297FP . PMID   19270432.
  13. ↑ Tsuchida R, Kubo M, Shintani N, Abe M, Köves K, Uetsuki K, et al. (April 2009). "Inhibitory effects of osemozotan, a serotonin 1A-receptor agonist, on methamphetamine-induced c-Fos expression in prefrontal cortical neurons". Biological & Pharmaceutical Bulletin. 32 (4): 728–31. doi: 10.1248/bpb.32.728 . PMID   19336914.
  14. ↑ Asano S, Matsuda T, Yoshikawa T, Somboonthum P, Tasaki H, Abe M, Baba A (May 1997). "Interaction of orally administered 5-[3-[((2S)-1,4-benzodioxan-2-ylmethyl)amino]propoxy]-1,3-benzodioxole (MKC-242) with 5-HT1A receptors in rat brain". Japanese Journal of Pharmacology. 74 (1): 69–75. doi: 10.1254/jjp.74.69 . PMID   9195299.
  15. ↑ Horiguchi N, Ago Y, Hasebe S, Higashino K, Asada K, Kita Y, et al. (November 2013). "Isolation rearing reduces mechanical allodynia in a mouse model of chronic inflammatory pain". Pharmacology, Biochemistry, and Behavior. 113: 46–52. doi:10.1016/j.pbb.2013.10.017. PMID   24161684. S2CID   19975118.
  16. ↑ McMillen BA, Scott SM, Williams HL, Sanghera MK (April 1987). "Effects of gepirone, an aryl-piperazine anxiolytic drug, on aggressive behavior and brain monoaminergic neurotransmission". Naunyn-Schmiedeberg's Archives of Pharmacology. 335 (4): 454–64. doi:10.1007/bf00165563. PMID   2439924. S2CID   23396992.
  17. ↑ Nakamura S, Ago Y, Hayashi A, Itoh S, Kakuda M, Hashimoto H, et al. (December 2006). "Modification of cocaine-induced behavioral and neurochemical effects by serotonin1A receptor agonist/antagonist in mice". Synapse. 60 (7): 479–84. doi:10.1002/syn.20323. PMID   16952156. S2CID   29597138.
  18. ↑ "Facts & Statistics | Anxiety and Depression Association of America, ADAA".
  19. 1 2 "Report: 1 in 5 of U.S. Adults on behavioral meds".
  20. ↑ "NIMH » Statistics".
This page is based on this Wikipedia article
Text is available under the CC BY-SA 4.0 license; additional terms may apply.
Images, videos and audio are available under their respective licenses.