5-HT2A-antagonist

Fibres from 5-HT neurons in the raphe nucleus innervate and yet, despite the observed 5-HT2A receptor link with neuronal excitation, appear to inhibit DA neurons in the SN (A9). Thus antagonism of 5-HT released onto them would increase their firing and so reduce the likelihood of EPSs, although how 5-HT2A antagonists can... 

Pehec, E. A., McFarlane, H. G., Maguschak, K., Price, B. Pluto, C. P. (2001). M100.907, a selective 5-HT2A antagonist, attenuates dopamine release in the rat medial prefrontal cortex. Brain Res. 888, 51-9. 

Eplivanserin (39) is a 5-HT2A antagonist initially developed for a broader spectrum of psychiatric disorders but that has been tested recently for insomnia. Within this latter indication, phase II studies showed benefits in sleep maintenance, but not in induction [9]. Compound 39 is currently in phase III, to assess the efficacy for the treatment of sleep maintenance insomnia, evaluating both sleep and daytime functioning [96]. 

Pruvanserin hydrochloride (41, EMR-62218/LY-2422347) is a 5-HT2A antagonist in phase II for the treatment of insomnia [99]. Safety and tolerability studies of 5 and 15 mg compared with placebo are ongoing and completion was expected in November 2006. 

Volinanserin (42, MDL-100907) is a selective 5-HT2A antagonist discontinued for schizophrenia and is currently undergoing phase II clinical trials for the treatment of insomnia. However, no data has been reported recently for this indication. 

P. L., McCloskey, T. C., Johnson, M.P., McCarty, D. R., Poirot, M., Senyah, Y., Siegel, B. W Widmaier, C. (1996) Preclinical characterization of the potential of the putative atypical antipsychotic MDL 100,907 as a potent 5-HT2A antagonist with a favorable CNS safety profile. The Journal of Pharmacology and Experimental Therapeutics, 277, 968—981. 

For example, it can be used to understand the SAR overlap " of the 5-HT2a antagonist and antipsychotic drug sertindole at hERG, sodium and calcium channels as shown in Fig. 10. 

Glennon RA, Metwally K, Dukat M, et al. Ketanserin and spiperone as templates for novel serotonin 5-HT2A antagonists. Curr Topics Med Chem 2002 2 539-558. 

The first member of the family to be described was the 5-HT2A receptor by means of radioligand-binding techniques (6). Since then, this receptor has become one of the most extensively studied in this family because of the efficacy of 5-HT2A antagonists in the treatment of schizophrenia. 

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