Eplivanserin

Pharmacodynamics Eplivanserin is an inverse agonist on the serotonin receptor subtype 5-HT2A. In contrast to older sedating drugs acting on 5-HT2A receptors (e.g., mirtazapine, clozapine, risperidone), eplivanserin has practically no affinity to dopamine, histamine and adrenergic receptors. Eplivanserin blocks the head-twitch response produced by the serotonin precursor 5-hydroxytryptophan (5-HTP), by serotonergic psychedelics (serotonin 5-HT2A receptor agonists) like DOI, and by serotonin 5-HT1A receptor antagonists like WAY-100635 and (S)-UH-301. The drug has been shown to upregulate serotonin 5-HT2A receptor expression, unlike many known serotonin 5-HT2A receptor antagonists, which paradoxically induce receptor downregulation. Relatedly, although eplivanserin given acutely can block the head-twitch response induced by various serotonergic drugs, it can also enhance the head-twitch response induced by 5-HTP and psychedelics like DOI when given on a sub-acute basis (given continuously and then withdrawn). Pharmacokinetics Eplivanserin is well-absorbed, with an absorption of more than 70%. Its elimination half-life is relatively long, with an average value of 50hours. ==Chemistry==

Synthesis ] The condensation between 2'-Fluoroacetophenone [445-27-2] (5) & 4-hydroxybenzaldehyde [123-08-0] (6) give a chalcone intermediate (also an enone), i.e. CID:53982926 (7). (2-chloroethyl)dimethylamine (CDMA) & acetone oxime are reacted together to give dimethylaminoacetoxime (DMA acetoxime), CID:16641114 (3). Convergent synthesis gives the product as a mixture of isomers. ==History==

Sanofi Aventis announced in December 2009 that it was withdrawing its application for approval of eplivanserin from both the U.S. Food and Drug Administration and the European Medicines Agency. ==Research==

Eplivanserin was under development for the treatment of anxiety disorders, insomnia, major depressive disorder, myocardial infarction (heart attack), and sleep apnea, but development for all indications was discontinued. Eplivanserin completed a clinical development program for insomnia that included two phase 3 clinical trials and almost 3,000patients. In a placebo controlled phase 2 trial with 351subjects, eplivanserin reduced the sleep latency by 39minutes (versus 26minutes under placebo). ==See also==