Adatanserin Explained

Adatanserin (WY-50,324, SEB-324) is a mixed 5-HT_1A receptor partial agonist and 5-HT_2A and 5-HT_2C receptor antagonist.^{[1] [2] [3]} It was under development by Wyeth as an antidepressant but was ultimately not pursued.^{[3] [4]}

Adantaserin has been shown to be neuroprotective against ischemia-induced glutamatergic excitotoxicity, an effect which appears to be mediated by blockade of the 5-HT_2A receptor.^[5]

Synthesis

2-Chloropyrimidine (1) reacts with piperazine (2), forming 2-(1-piperazinyl)pyrimidine (3). Treatment with the phthalimide derivative N-(2-bromoethyl)phthalimide (4) in an alkylation reaction produces (5), which is deprotected using hydrazine to give the primary amine (6). Amide formation with the acid chloride of 1-adamantanecarboxylic acid yields adatanserin.^{[6] [3]}

See also

• Flibanserin

Notes and References

1. Singh A, Lucki I . Antidepressant-like activity of compounds with varying efficacy at 5-HT1A receptors . Neuropharmacology . 32 . 4 . 331–40 . April 1993. 8497336 . 10.1016/0028-3908(93)90153-T. 38611829 .
2. Kleven MS, Koek W . Pharmacological characterization of in vivo properties of putative mixed 5-HT1A agonist/5-HT2A/2C antagonist anxiolytics. I. Antipunishment effects in the pigeon . The Journal of Pharmacology and Experimental Therapeutics . 276 . 2 . 388–97 . February 1996. 8632301 .
3. Abou-Gharbia MA, Childers WE, Fletcher H . Synthesis and SAR of adatanserin: novel adamantyl aryl- and heteroarylpiperazines with dual serotonin 5-HT(1A) and 5-HT(2) activity as potential anxiolytic and antidepressant agents . Journal of Medicinal Chemistry . 42 . 25 . 5077–94 . December 1999. 10602693 . 10.1021/jm9806704. etal.
4. Book: Stahl, S. M. . Essential psychopharmacology: neuroscientific basis and practical application . Cambridge University Press . Cambridge, UK . 2000 . 0-521-64615-4 . registration . 262 . adatanserin. .
5. Dawson LA, Galandak J, Djali S . Attenuation of ischemic efflux of endogenous amino acids by the novel 5-HT(1A)/5-HT(2) receptor ligand adatanserin . Neurochemistry International . 40 . 3 . 203–9 . March 2002. 11741003 . 10.1016/S0197-0186(01)00082-1. 24104458 .
6. US . 5482940 . Magid A.-M., et al. . Use of aryl- and heteroaryl piperazinyl carboxamides in the treatment of various central nervous system disorders . patent . 1996-01-09 . 1993-04-19 . 1990-03-14 . American Home Products Corp.