Osemozotan

Osemozotan

Legal status
Legal status	In general: uncontrolled
Identifiers
IUPAC name 5-(3-[((2S)-1,4-benzodioxan-2-ylmethyl)amino]propoxy)-1,3-benzodioxole
CAS Number	137275-81-1^Y HCl: 137275-80-0^Y
PubChem CID	198746
ChemSpider	172023^N
UNII	M65825806Q HCl: F0WKFYPQL8^Y
CompTox Dashboard (EPA)	DTXSID00929762
Chemical and physical data
Formula	C19H21NO5
Molar mass	343.379 g·mol^−1
3D model (JSmol)	Interactive image
SMILES C1[C@@H](OC2=CC=CC=C2O1)CNCCCOC3=CC4=C(C=C3)OCO4
InChI 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^N Key:MEEQBDCQPIZMLY-HNNXBMFYSA-N^N
^NY (what is this?)  (verify)

Osemozotan (MKC-242) is a selective 5-HT_1A receptor agonist with some functional selectivity, acting as a full agonist at presynaptic and a partial agonist at postsynaptic 5-HT_1A receptors.^[1] 5-HT_1A receptor stimulation influences the release of various neurotransmitters including serotonin, dopamine, norepinephrine, and acetylcholine.^[2] 5-HT_1A receptors are inhibitory G protein-coupled receptor.^[3]

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-HT_1A 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-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.^[2] Even with repeated exposure of 5-HT_1A 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 t_max 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-HT_1A, 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-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.^[2][6]

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 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-HT_1A 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-HT_1A 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-HT_1A 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

• Piclozotan
• Robalzotan
• Sarizotan

References

1. 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. 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. 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. 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. 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. "Report: 1 in 5 of U.S. Adults on behavioral meds".
20. "NIMH » Statistics".