Studies with selective antagonists and mutant mice strongly suggest that 5-HT_2C receptor activation elicits hypophagia in rodents. This mechanism is thought to be clinically relevant as non-selective 5-HT_2C receptor agonists such as mCPP and fenfluramine reduce appetite and body weight in normal and obese patients and volunteers. Further evidence for the utility of this mechanism, however, awaits the development of selective 5-HT_2C receptor agonists.

VER-8775 (1-Piperazinecarbothioic acid, S-[[4-[[[(1,1-dimethylethyl) amino]carbonyl]oxy]phenyl]methyl] ester) was profiled at the INI unedited isoform of the human and rat 5-HT_2C receptor in binding studies and at the human, rat and mouse VSV isoform of the 5-HT_2C receptor for functional activity using Fluorescence Imaging Plate Reader (FLIPR) methodology. At the h5-HT_2C receptor, VER-8775 has high binding affinity (pKi 8.22) and possesses substantial agonist potency (pEC₅₀ 7.8) and efficacy (73%). VER-8775 has greater than 100 fold binding selectivity over the h5-HT_2B receptor (pKi 5.4) at which it had negligible agonist efficacy (5%). Furthermore, the compound displayed only weak agonist efficacy (pEC₅₀ 6.9, 28%) at h5-HT_2A receptors at which it also had a substantially lower binding affinity (pKi 6.9) than at the h5-HT_2C receptors. In wide binding studies, VER-8775 had > 100 fold binding selectivity for 5-HT_2C over 5-HT_1A , 5-HT_1B , 5-HT_1D , 5-HT₃ , 5-HT₄ , 5-HT_5A , 5-HT₆ and 5-HT₇ receptor subtypes and over 49 other receptors.

Singly housed male C57B mice (25-30 g) under a 12hr light/dark cycle (lights on 08:00hr), in a temperature (20 ± 2°C) and humidity (55 ± 15%) controlled environment with ad libitum access to laboratory chow were habituated to the daily consumption of a palatable mash meal (1 part chow /2 parts water by weight). Oral administration of VER-8775 to groups of 7 mice, reduced food intake with a minimum effective dose of 10 mg/kg over 30 mins..

Male C57B mice housed in groups of 8 and fed a high fat diet (HFD) (Western Affluent Diet, 43% calories by fat) had a 20% higher body weight than chow fed, age matched, controls after 12 weeks. Despite continued access to the HFD, treatment with VER-8775 10 and 15 mg/kg po bid reduced body weight over a 28 day period, (Mean ± sem body weight on day 1 (g): Veh treated mice 39.5 ±1.6 vs VER 15 mg/kg bid 39.5 ± 1.1 (ns), Day 28: Veh 39.7 ± 1.95, VER 15 mg/kg bid 34.6 ± 0.77 P<0.05 by Dunnett's test and 1 way ANOVA on day 28, following significant dose x day 2 way ANOVA, n=8 per group). Indeed, the higher dose fully reversed diet-induced obesity as did the clinically effective anorectic agent, d-fenfluramine.

In conclusion, VER-8775 is a highly selective 5-HT_2C receptor agonist with oral efficacy in a mouse model of obesity, further supporting the potential utility of 5-HT_2C receptor agonists in the treatment of clinical obesity. In addition, VER-8775 is a highly selective agonist tool that may be of use in defining the significance of the 5-HT_2C receptor.