sb-243213 and Weight-Gain

Substantial increases in body weight can be induced by several antipsychotic drugs, most notably olanzapine and clozapine. Antagonism at certain receptors, particularly 5-HT2C and histamine H1 receptors, is implicated in this effect.. We have investigated the contribution of effects at these receptors to olanzapine-induced weight gain occurring over 5 days following daily intraperitoneal drug injections in groups of eight female rats.. Olanzapine (2 mg/kg) and the 5-HT2C antagonist SB 243213 (1 mg/kg), but not the histamine H1 antagonist mepyramine (1 mg/kg), produced significant increases in percentage body weight above vehicle; olanzapine showed a significantly greater effect than SB 243213. Haloperidol (0.1 mg/kg) alone or with mepyramine had no significant effects on weight gain, while with SB 243213 and with both SB 243213 and mepyramine, it showed olanzapine-like increases in weight.. These results suggest that 5-HT2C receptor antagonism or inverse agonism, in the presence of D2 receptor antagonism, may contribute to olanzapine-induced weight gain.

Topics: Analysis of Variance; Animals; Behavior, Animal; Benzodiazepines; Dopamine Antagonists; Drug Interactions; Female; Haloperidol; Histamine H1 Antagonists; Indoles; Olanzapine; Pyridines; Pyrilamine; Rats; Receptor, Serotonin, 5-HT2C; Receptors, Histamine H1; Selective Serotonin Reuptake Inhibitors; Serotonin 5-HT2 Receptor Agonists; Time Factors; Weight Gain

Robust pharmaceutical treatment of obesity has been limited by the undesirable side-effect profile of currently marketed therapies. This paper describes the synthesis and optimization of a new class of pyrazinoisoindolone-containing, selective 5-HT2C agonists as antiobesity agents. Key to optimization of the pyrazinoisoindolone core was the identification of the appropriate substitution pattern and functional groups which led to the discovery of (R)-9-ethyl-1,3,4,10b-tetrahydro-7-trifluoromethylpyrazino[2,1-a]isoindol-6(2H)-one (58), a 5-HT2C agonist with >300-fold functional selectivity over 5-HT2B and >70-fold functional selectivity over 5-HT2A. Oral dosing of 58 reduced food intake in an acute rat feeding model, which could be completely reversed by a selective 5-HT2C antagonist and caused a reduction in body weight gain in a 4-day rat model.

Topics: Administration, Oral; Animals; Anti-Obesity Agents; Blood-Brain Barrier; Cell Line; Conditioning, Operant; Feeding Behavior; Humans; Indoles; Isoindoles; Male; Mice; Necrosis; Parietal Cells, Gastric; Pyrazines; Radioligand Assay; Rats; Rats, Sprague-Dawley; Serotonin 5-HT2 Receptor Agonists; Stereoisomerism; Weight Gain