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Title: Osemozotan  
Author: World Heritage Encyclopedia
Language: English
Subject: Sarizotan, 5-HT1A receptor, PNU-142633, RS-56812, PHA-57378
Publisher: World Heritage Encyclopedia


Systematic (IUPAC) name
Clinical data
Legal status
  • Uncontrolled
CAS number  YesY
ATC code ?
ChemSpider  N
Chemical data
Formula C20H23NO4 
Mol. mass 341.400 g/mol

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] Osemozotan has antidepressant, anxiolytic, antiobsessional, serenic, and analgesic effects in animal studies,[4][5][6] ,[2] and 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 abused stimulants such as cocaine and methamphetamine.[9][10][11][12][13]


The target of Osemozotan is 5-HT1A receptors. This molecules bind with almost 1000 times greater affinity to 5-HT1A receptors than most other 5-HT, dopamine, or adrenergic receptors.[2] With repeated exposure of Osemozotan at the 5-HT1A receptors, there seems to be no change in the number of receptors, which is not typically seen with pharmaceutical agonists.[14]


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 was 2,943 ng x hr/mL and the half-life was 1.3 hours.[6] 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.[6] 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. It must be noted that in these studies there was a difference in dosage amount necessary for the indication it is used.[6] Osemozotan has not been found to be metabolized to 1-(2-pyrimidinyl)-piperazine, a common metabolite found with the azapirone class of medications.[6] 1-(2-pyrimidinyl)-piperazine has affinity for receptors other than 5-HT1A, decreasing its specificity and increasing the risk of unwanted effects.[6] Since Osemozotan does not express this metabolite, it has greater specificity to 5-HT1A compared to other anxiolytic medications.


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.[2][6]


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 and decrease mechanical allodynia.[2][15]

Aggressive Behavior

Osemozotan was found to decrease the number of fighting incidences 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 within the mice.[6]

Anxiety and Depression

5-HT 1A receptors when stimulated have shown to have anxiolytic and antidepressant pharmacologic effects.[2]

Obsessive-Compulsive Disorder (OCD)

Obsessive-Compulsive patients have been found to have increased 5-HT levels within the brain.[16][17] 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.[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 of cocaine may stem from action of the 5-HT 1A receptor.[18][19] 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.[20]

Prevalence of Mental Disease States

About 18% of American adults suffer from some type of anxiety disorder [21] and 1 in 5 adults in the United States are on some type of medication to help control or improve their behavior.[22] 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.[22] Around 60 billion dollars are spent annually for treatments dealing with mental illnesses.[23]

See also


  1. ^ Matsuda, T.; Yoshikawa, T.; Suzuki, M.; Asano, S.; Somboonthum, P.; Takuma, K.; Nakano, Y.; Morita, T.; Nakasu, Y.; Kim, H. S.; Egawa, M.; Tobe, A.; Baba, A. (1995). "Novel benzodioxan derivative, 5-(3-((2S)-1,4-benzodioxan-2- ylmethyl)aminopropoxy)-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): 357–366.  
  2. ^ a b c d e f Matsuda, Toshio. "Neuropharmacologic Studies on the Brain Serotonin1A Receptor Using the Selective Agonist Osemozotan." Biol.Pharm.Bull. 36.12 (2013): 1871-882.
  3. ^ Saudou F, Hen R. 5-Hydroxytryptamine receptor subtypes in vertebrates and invertebrates. Neurochem. Int., 25, 503-532 (1994)
  4. ^ Abe, M.; Tabata, R.; Saito, K.; Matsuda, T.; Baba, A.; Egawa, M. (1996). "Novel benzodioxan derivative, 5-3-((2S)-1,4-benzodioxan-2-ylmethyl) aminopropoxy-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.  
  5. ^ Sakaue, M.; Ago, Y.; Sowa, C.; Koyama, Y.; Baba, A.; Matsuda, T. (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): 141–144.  
  6. ^ a b c d e f g h i j k l 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. (2000). "Postsynaptic 5-hydroxytryptamine1A receptor activation increases in vivo dopamine release in rat prefrontal cortex". British Journal of Pharmacology 129 (5): 1028–1034.  
  8. ^ Ago, Y.; Koyama, Y.; Baba, A.; Matsuda, T. (2003). "Regulation by 5-HT1A receptors of the in vivo release of 5-HT and DA in mouse frontal cortex". Neuropharmacology 45 (8): 1050–1056.  
  9. ^ Ago, Y.; Nakamura, S.; Uda, M.; Kajii, Y.; Abe, M.; Baba, A.; Matsuda, T. (2006). "Attenuation by the 5-HT1A receptor agonist osemozotan of the behavioral effects of single and repeated methamphetamine in mice". Neuropharmacology 51 (4): 914–922.  
  10. ^ Ago, Y.; Nakamura, S.; Hayashi, A.; Itoh, S.; Baba, A.; Matsuda, T. (2006). "Effects of osemozotan, ritanserin and azasetron on cocaine-induced behavioral sensitization in mice". Pharmacology, Biochemistry, and Behavior 85 (1): 198–205.  
  11. ^ Ago, Y.; Nakamura, S.; Baba, A.; Matsuda, T. (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.  
  12. ^ Tsuchida, R.; Kubo, M.; Kuroda, M.; Shibasaki, Y.; Shintani, N.; Abe, M.; Köves, K.; Hashimoto, H.; Baba, A. (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.  
  13. ^ Tsuchida, R.; Kubo, M.; Shintani, N.; Abe, M.; Köves, K.; Uetsuki, K.; Kuroda, M.; Hashimoto, H.; Baba, A. (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): 728–731.  
  14. ^ Asano, Shoichi, Toshio Matsuda, Takashi Yoshikawa, Pranee Somboonthum, Hatsue Tasaki, Michikazu Abe, and Akemichi Baba. "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." Jpn. J. Pharmacol. 74 (1997): 69-75.
  15. ^ Horiguchi, Naotaka, Yukio Ago, Shigeru Hasebe, Kosuke Higashino, Kazuki Asada, Yuki Kita, Kazuhiro Takuma, and Toshio Matsuda. "Isolation Rearing Reduces Mechanical Allodynia in a Mouse Model of Chronic Inflammatory Pain." Pharmacology, Biochemistry and Behavior 113 (2013): 46-52.
  16. ^ Matsuda T, Yoshikawa T, Suzuki M, Asano S, Somoboonthum P, Takuma K, Nahano Y, Morita T, Nakasu Y, Kim HS, Egawa M, Tobe A and Baba A: 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 serotonin1A receptors. Jpn J Pharmacol 69, 357-366 (1995)
  17. ^ McMillen BA, Scott SM, Williams HL and Sanghera MK: Effects of gepirone, an aryl-piperazine anxiolytic drug, on aggressive behavior and brain monoaminergic neurotransmission. Naunyn Schmiedebergs Arch Pharmacol 335, 454-464(1987)
  18. ^ Ago Y, Nakamura S, Hayashi A, Itoh S, Baba A, Matsuda T. Effects of osemozotan, ritanserin and azasetron on cocaine-induced behavioral sensitization in mice. Pharmacol. Biochem. Behav., 85, 198-205 (2006)
  19. ^ Nakamura S, Ago Y, Hayashi A, Itoh S, Kakuda M, Hashimoto H, Baba A, Matsuda T. Modification of cocaine-induced behavioral and neurochemical effects by serotonin1A receptor agonist/antagonist in mice. Synapse, 60, 479-484 (2006)
  20. ^ Ago Y, Nakamura S, Uda M, Kajii Y, Abe M, Baba A, Matsuda T. Attenuation by the 5-HT 1A receptor agonist osemozotan of the behavioral effects of single and repeated methamphetamine in mice. Neuropharmacology, 51, 914-922 (2006).
  21. ^
  22. ^ a b
  23. ^
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