Volinanserin

Last updated

Volinanserin
Volinanserin.svg
Clinical data
Other namesMDL-100,907; M100907
ATC code
  • None
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)
  • c3cc(F)ccc3CCN(CC2)CCC2C(O)c(c1OC)cccc1OC

Volinanserin (INN; 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] [2] [3] It was also tested in clinical trials as a potential antipsychotic, [4] [5] antidepressant, [6] and treatment for insomnia but was never marketed. [7]

Contents

CNS Review: [8]

Synthesis

The synthesis of volinanserin has been reported. [9] [10] [11] [12] 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. ↑ 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.
  2. ↑ 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.
  3. ↑ 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.
  4. ↑ 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.
  5. ↑ Charney DS, Nestler PS, Sklar P, Buxbaum JD (July 2013). Neurobiology of Mental Illness. OUP USA. p. 767. ISBN   9780199934959.
  6. ↑ 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.
  7. ↑ 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.
  8. ↑ Schmidt, C. J., Kehne, J. H., Carr, A. A. (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. ↑ 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.
  10. ↑ 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.
  11. ↑ 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.
  12. ↑ 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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