Volinanserin

Last updated

Volinanserin
Volinanserin.svg
Clinical data
Other namesMDL-100,907; MDL-100907; MDL100907; M100907; M-100907; M-100,907
Routes of
administration 		Oral [1] [2]
Drug class Serotonin 5-HT2A receptor antagonist
ATC code
  • None
Pharmacokinetic data
Onset of action Tmax Tooltip Time to peak levels: 1–2.5 hours [3] [4]
Elimination half-life 6.6 hours (range 4.5–9.8 hours) [2] [5] [6] [7] [3] [4]
Identifiers
  • (R)-(2,3-dimethoxyphenyl)-[1-[2-(4-fluorophenyl)ethyl]-4-piperidyl]methanol
CAS Number
PubChem CID
IUPHAR/BPS
ChemSpider
UNII
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard 100.123.797 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C22H28FNO3
Molar mass 373.468 g·mol−1
3D model (JSmol)
  • COC1=CC=CC(=C1OC)[C@@H](C2CCN(CC2)CCC3=CC=C(C=C3)F)O
  • InChI=1S/C22H28FNO3/c1-26-20-5-3-4-19(22(20)27-2)21(25)17-11-14-24(15-12-17)13-10-16-6-8-18(23)9-7-16/h3-9,17,21,25H,10-15H2,1-2H3/t21-/m1/s1
  • Key:HXTGXYRHXAGCFP-OAQYLSRUSA-N

Volinanserin (INN Tooltip International Nonproprietary Name; developmental code MDL-100,907) is a highly selective 5-HT2A receptor antagonist that is frequently used in scientific research to investigate the function of the 5-HT2A receptor. [1] [8] [9] [10] [11] It was also tested in clinical trials as a potential antipsychotic, [12] [13] antidepressant, [14] and treatment for insomnia but was never marketed. [1] [15] The drug reached phase 3 trials for schizophrenia and insomnia prior to the discontinuation of its development in the late 2000s. [1] It is taken orally. [1]

Contents

Pharmacology

Pharmacokinetics

The time to peak levels of volinanserin is 1 to 2.5 hours. [3] [4] The elimination half-life of volinanserin is 6.6 hours, with a range of 4.5 to 9.8 hours. [2] [5] [6] [7] [3] [4] However, cortical serotonin 5-HT2A receptor occupancy with volinanserin measured by positron emission tomography (PET) imaging lasts much longer than its circulating elimination half-life would imply. [2] [5] [6] [7] [3]

Chemistry

Synthesis

The synthesis of volinanserin has been reported. [16] [17] [18] [19] Beginning with protection of ethyl isonipecotate (1) with Boc anhydride gives ethyl N-Boc-4-piperidinecarboxylate (2). Ester-amide interchange with N-methoxymethylamine HCl in the presence of carbonyldiimidazole (CDI) coupling agent gives 1-Boc-4-[methoxy(methyl)carbamoyl]piperidine (3). Weinreb ketone synthesis occurs upon benzoylation with 1,2-dimethoxybenzene (4) to give 1-Boc-4-(2,3-dimethoxybenzoyl)piperidine (5). Acid removal of the urethane protecting group gives (2,3-dimethoxyphenyl)-piperidin-4-ylmethanone (6). The reduction of the ketone with sodium borohydride leads to (2,3-dimethoxyphenyl)-piperidin-4-ylmethanol (7). Resolution of the alcohol gives (8). SN2 alkylation of the secondary nitrogen with 4-fluorophenethyl bromide (9) completes the synthesis of volinanserin (10).

Synthesis of volinanserin Volinanserin synthesis.svg
Synthesis of volinanserin

See also

References

  1. 1 2 3 4 5 "Volinanserin". AdisInsight. 13 March 2009. Retrieved 16 January 2026.
  2. 1 2 3 4 Teegarden BR, Al Shamma H, Xiong Y (2008). "5-HT(2A) inverse-agonists for the treatment of insomnia". Curr Top Med Chem. 8 (11): 969–976. doi:10.2174/156802608784936700. PMID   18673166. The plasma half-life for Volinanserin is ~6.6 hr and according to Gründer et al. [82] the receptor occupancy half-life greatly exceeds this.
  3. 1 2 3 4 5 Gründer G, Yokoi F, Offord SJ, Ravert HT, Dannals RF, Salzmann JK, et al. (September 1997). "Time course of 5-HT2A receptor occupancy in the human brain after a single oral dose of the putative antipsychotic drug MDL 100,907 measured by positron emission tomography". Neuropsychopharmacology. 17 (3): 175–185. doi:10.1016/S0893-133X(97)00044-4. PMID   9272484. MDL 100,907 is rapidly absorbed following oral administration with the tmax occurring at 1–2.5 hours post dose. The plasma half-life is in the range of 4.5–9.8 hours with a mean half-life of 6.6 hours. Taking into account the half-life of 6.6 hours, it can be concluded that the receptor occupancy half-life of MDL 100,907 is considerably longer than the plasma half-life.
  4. 1 2 3 4 Andrée B, Nyberg S, Ito H, Ginovart N, Brunner F, Jaquet F, et al. (August 1998). "Positron emission tomographic analysis of dose-dependent MDL 100,907 binding to 5-hydroxytryptamine-2A receptors in the human brain". J Clin Psychopharmacol. 18 (4): 317–323. doi:10.1097/00004714-199808000-00012. PMID   9690698. The pharmacokinetic parameters area under the curve and peak plasma concentration increased linearly with dose, with rapid absorption and a 6- to 9-hour elimination half-life. [...] For the three highest doses (9, 18, and 72 mg), plasma concentrations were sufficient to show that MDL 100,907 was eliminated from plasma in a monoexponential mode with a mean half-life of 5.5 to 8.8 hours. [...] The time to maximal plasma concentration (Tmax) was 1 to 2.5 hours, and the PET
  5. 1 2 3 Landolt HP, Wehrle R (May 2009). "Antagonism of serotonergic 5-HT2A/2C receptors: mutual improvement of sleep, cognition and mood?". Eur J Neurosci. 29 (9): 1795–1809. doi:10.1111/j.1460-9568.2009.06718.x. PMID   19473234. The plasma half-life of eplivanserin and volinanserin is 6–8 h, whereas receptor occupancy lasts considerably longer and hangover effects such as daytime sedation cannot be excluded (Gru¨nder et al., 1997; Teegarden et al., 2008).
  6. 1 2 3 Casey AB, Cui M, Booth RG, Canal CE (June 2022). ""Selective" serotonin 5-HT2A receptor antagonists". Biochem Pharmacol. 200 115028. doi:10.1016/j.bcp.2022.115028. PMC   9252399 . PMID   35381208. Positron emission tomography (PET) studies in humans confirmed that M100,907 exhibited high levels of apparent 5-HT2AR occupancy in the cortex (74) for over 24 hours, far outlasting its presence in plasma (75).
  7. 1 2 3 Piel M, Vernaleken I, Rösch F (November 2014). "Positron emission tomography in CNS drug discovery and drug monitoring". J Med Chem. 57 (22): 9232–9258. doi:10.1021/jm5001858. PMID   25144329. In an exemplary study, Gründer et al. established the relationship of receptor occupancy and plasma levels in healthy subjects after single oral doses (10 or 20 mg) of volinanserin, a potent 5-HT2A receptor antagonist.74 N-[11C]Methylspiperone was applied to determine the receptor occupancy in the frontal cortex, while plasma levels were determined using HPLC and mass spectroscopy (Figure 20). Interestingly, although a fast plasma washout was observed for both doses, stable 5-HT2A receptor occupancies of about 85% occurred for 24 h for the 20 mg dose, whereas the 10 mg dose resulted in this occupancy for only 8 h, followed by a slow decrease to 70%. Hence, this study showed that there is a discrepancy between the central pharmacodynamic effects of volinanserin and its peripheral pharmacokinetics.
  8. ↑ Schmidt CJ, Kehne JH, Carr AA (March 1997). "MDL 100,907: A Selective 5-HT 2A Receptor Antagonist for the Treatment of Schizophrenia". CNS Drug Reviews. 3 (1): 49–67. doi:10.1111/j.1527-3458.1997.tb00316.x.
  9. ↑ Schmidt CJ, Fadayel GM, Sullivan CK, Taylor VL (November 1992). "5-HT2 receptors exert a state-dependent regulation of dopaminergic function: studies with MDL 100,907 and the amphetamine analogue, 3,4-methylenedioxymethamphetamine". European Journal of Pharmacology. 223 (1): 65–74. doi:10.1016/0014-2999(92)90819-P. PMID   1362159.
  10. ↑ Herth MM, Kramer V, Piel M, Palner M, Riss PJ, Knudsen GM, et al. (April 2009). "Synthesis and in vitro affinities of various MDL 100907 derivatives as potential 18F-radioligands for 5-HT2A receptor imaging with PET". Bioorganic & Medicinal Chemistry. 17 (8): 2989–3002. CiteSeerX   10.1.1.519.5663 . doi:10.1016/j.bmc.2009.03.021. PMID   19329329.
  11. ↑ Nic Dhonnchadha BA, Fox RG, Stutz SJ, Rice KC, Cunningham KA (April 2009). "Blockade of the serotonin 5-HT2A receptor suppresses cue-evoked reinstatement of cocaine-seeking behavior in a rat self-administration model". Behavioral Neuroscience. 123 (2): 382–96. doi:10.1037/a0014592. PMC   3830454 . PMID   19331461.
  12. ↑ Offord SJ, Wong DF, Nyberg S (August 1999). "The role of positron emission tomography in the drug development of M100907, a putative antipsychotic with a novel mechanism of action". Journal of Clinical Pharmacology. 39 (S1): 17S –24S. doi:10.1002/j.1552-4604.1999.tb05933.x. PMID   10434243. S2CID   21311671.
  13. ↑ Charney DS, Nestler PS, Sklar P, Buxbaum JD (July 2013). Neurobiology of Mental Illness. OUP USA. p. 767. ISBN   978-0-19-993495-9.
  14. ↑ Marek GJ, Martin-Ruiz R, Abo A, Artigas F (December 2005). "The selective 5-HT2A receptor antagonist M100907 enhances antidepressant-like behavioral effects of the SSRI fluoxetine". Neuropsychopharmacology. 30 (12): 2205–15. doi: 10.1038/sj.npp.1300762 . PMID   15886717.
  15. ↑ Teegarden BR, Al Shamma H, Xiong Y (2008). "5-HT(2A) inverse-agonists for the treatment of insomnia". Current Topics in Medicinal Chemistry. 8 (11): 969–76. doi:10.2174/156802608784936700. PMID   18673166.
  16. ↑ Németh K, Palkó R, Kovács P, Visy J (January 2014). "Development of novel chiral capillary electrophoresis methods for the serotonin receptor (5-HT2A) antagonist MDL 100,907 (volinanserin) and for its key intermediate compound". Journal of Pharmaceutical and Biomedical Analysis. 88: 579–583. doi:10.1016/j.jpba.2013.10.017. PMID   24216279.
  17. ↑ WO 1991018602,Carr AA, Kane JM, Hay DA,"(+)-α-(2,3-Dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl]-4-piperidinemethanol",published 12 December 1991, assigned to Merrell Dow Pharmaceuticals Inc.
  18. ↑ Huang Y, Mahmood K, Mathis CA (1999). "An efficient synthesis of the precursors of [11C]MDL 100907 labeled in two specific positions". Journal of Labelled Compounds and Radiopharmaceuticals. 42 (10): 949–957. doi:10.1002/(SICI)1099-1344(199910)42:10<949::AID-JLCR253>3.0.CO;2-S.
  19. ↑ WO 1998004289,Blackburn TP,"Pharmaceutical composition containing a 5HT2c antagonist and a D2 antagonist",published 5 February 1998, assigned to SmithKline Beecham Ltd.
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