Volinanserin Explained

Volinanserin (INN) (developmental code name MDL-100,907) is a highly selective 5-HT_2A receptor antagonist that is frequently used in scientific research to investigate the function of the 5-HT_2A 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]

Synthesis

The protection of Ethyl isonipecotate [1126-09-6] (1) with Boc anhydride gives ethyl n-boc-4-piperidinecarboxylate [142851-03-4] (2). Ester-amide interchange with N-Methoxymethylamine HCl: [6638-79-5] in the presence of CDI coupling agent gives 1-Boc-4-[methoxy(methyl)carbamoyl]piperidine [139290-70-3] (3). Weinreb ketone synthesis occurs upon benzoylation with 1,2-Dimethoxybenzene [91-16-7] (4) to give 1-Boc-4-(3,4-dimethoxybenzoyl)piperidine, [2322526-86-1] CID:139510111 (5). Acid removal of the urethane protecting group gives (3,4-dimethoxyphenyl)-piperidin-4-ylmethanone [742665-98-1] (6). The reduction of the ketone with sodium borohydride leads to (3,4-Dimethoxyphenyl)-piperidin-4-ylmethanol, CID:24261124 (7). Resolution of the alcohol gives (8). Sn2 alkylation of the secondary nitrogen with 4-Fluorophenethyl bromide [332-42-3] (9) completed the synthesis of Volinanserin (10).

See also

• Glemanserin
• Pruvanserin
• Roluperidone
• Lenperone
• Lidanserin
• Ketanserin
• Ritanserin
• Eplivanserin
• Pimavanserin

Notes and References

1. Schmidt CJ, Fadayel GM, Sullivan CK, Taylor VL . 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 . November 1992 . 1362159 . 10.1016/0014-2999(92)90819-P .
2. Herth MM, Kramer V, Piel M, Palner M, Riss PJ, Knudsen GM, Rösch F . 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 . April 2009 . 19329329 . 10.1016/j.bmc.2009.03.021 . 10.1.1.519.5663 .
3. Nic Dhonnchadha BA, Fox RG, Stutz SJ, Rice KC, Cunningham KA . 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 . April 2009 . 19331461 . 3830454 . 10.1037/a0014592 .
4. Offord SJ, Wong DF, Nyberg S . 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 . August 1999 . 10434243 . 10.1002/j.1552-4604.1999.tb05933.x . 21311671 .
5. Book: Neurobiology of Mental Illness . Charney DS, Nestler PS, Sklar P, Buxbaum JD . July 2013 . OUP USA. 767 . 9780199934959.
6. Marek GJ, Martin-Ruiz R, Abo A, Artigas F . The selective 5-HT2A receptor antagonist M100907 enhances antidepressant-like behavioral effects of the SSRI fluoxetine . Neuropsychopharmacology . 30 . 12 . 2205–15 . December 2005 . 15886717 . 10.1038/sj.npp.1300762 . free .
7. Teegarden BR, Al Shamma H, Xiong Y . 5-HT(2A) inverse-agonists for the treatment of insomnia . Current Topics in Medicinal Chemistry . 8 . 11 . 969–76 . 2008 . 18673166 . 10.2174/156802608784936700 .