A new series of quinazolinone derivatives was synthesized and evaluated as nonimidazole H 3 receptor inverse agonists. 2-Methyl-3-(4-[[3-(1-pyrrolidinyl)propyl]oxy]phenyl)-5-(trifluoromethyl)-4(3 H)-quinazolinone ( 1) was identified as a promising derivative for further evaluation following optimization of key parameters. Compound 1 has potent H 3 inverse agonist activity and excellent selectivity over other histamine receptor subtypes and a panel of 115 unrelated diverse binding sites. Compound 1 also shows satisfactory pharmacokinetic profiles and brain penetrability in laboratory animals. Two hours after oral administration of 30 mg/kg of 1 to SD rats, significant elevation of brain histamine levels was observed where the brain H 3 receptor was highly occupied (>90%). On the basis of species differences in P-glycoprotein (P-gp) susceptibility of 1 between human and rodent P-gps, the observed rodent brain permeability of 1 is significantly limited by P-gp mediated efflux in rodents, whereas the extent of P-gp mediated efflux in humans should be very small or negligible. The potential of 1 to be an efficacious drug was demonstrated by its excellent brain penetrability and receptor occupancy in P-gp-deficient CF-1 mice.

Neuropeptide Y (NPY) is thought to have a major role in the physiological control of energy homeostasis. Among five NPY receptors described, the NPY Y5 receptor (Y5R) is a prime candidate to mediate some of the effects of NPY on energy homeostasis, although its role in physiologically relevant rodent obesity models remains poorly defined. We examined the effect of a potent and highly selective Y5R antagonist in rodent obesity and dietary models. The Y5R antagonist selectively ameliorated diet-induced obesity (DIO) in rodents by suppressing body weight gain and adiposity while improving the DIO-associated hyperinsulinemia. The compound did not affect the body weight of lean mice fed a regular diet or genetically obese leptin receptor-deficient mice or rats, despite similarly high brain Y5R receptor occupancy. The Y5R antagonist acts in a mechanism-based manner, as the compound did not affect DIO of Y5R-deficient mice. These results indicate that Y5R is involved in the regulation and development of DIO and suggest utility for Y5R antagonists in the treatment of obesity.antiobesity effect ͉ Y5R-deficient mice ͉ receptor occupancy N europeptide Y (NPY), a 36-aa peptide neurotransmitter, is one of the most potent orexigenic substances when injected into the brain. NPY expression is widely distributed in the CNS, including the hypothalamus, a region involved in energy homeostasis (1). NPY content and mRNA levels in the hypothalamus respond to feeding status, including food deprivation and refeeding (2, 3). Chronic central infusion of NPY in rodents results in a syndrome similar to that in some genetic obesity models, characterized by hyperphagia, insulin resistance, hyperinsulinemia, and reduced thermogenic activity in brown adipose tissue (4). NPY is, therefore, thought to have a major role in the physiological control of energy homeostasis, making it a target for the development of antiobesity agents.Five types of NPY receptors have been characterized (5). Pharmacological data suggest that the NPY Y5 receptor (Y5R) is involved in feeding regulation. For example, functional and binding activities of different peptide agonists at the Y5R in vitro correlated strongly with their efficacy in stimulating food intake (6). Administration of Y5R antagonists suppressed Y5R agonist-induced feeding (7), and mice lacking the Y5R showed a diminished response to exogenously administered Y5R agonists (8). The Y5R is also reported to regulate brown fat thermogenesis and energy expenditure (9). In addition, chronic intracerebroventricular administration of a Y5R-specific agonist, D-Trp-34NPY, produces obesity (10). These findings suggest that the Y5R is involved in the development of obesity. However, the physiological role of the Y5R in obesity models, rather than models that rely on exogenously added Y5R agonists, remains undefined.We reported that orally administered Y5R antagonist [2-(3,3-dimethyl-1-oxo-4H-1H-xanthen-9-yl)-5,5-dimethyl-cyclohexane-1,3-dione] reduced Y5R agonist-induced feeding and Y5R agonist-induced obesity (7, ...

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Objective:To further address the function of the Y5 receptor in energy homeostasis, we investigated the effects of a novel spironolactone Y5 antagonist in diet-induced obese (DIO) mice. Methods and Procedures: Male C57BL/6 or Npy5r −/− mice were adapted to high-fat (HF) diet for 6-10 months and were submitted to three experimental treatments. First, the Y5 antagonist at a dose of 10 or 30 mg/kg was administered for 1 month to DIO C57BL/6 or Npy5r −/− mice. Second, the Y5 antagonist at 30 mg/kg was administered for 1.5 months to DIO C57BL/6 mice, and insulin sensitivity was evaluated using an insulin tolerance test. After a recovery period, nuclear magnetic resonance measurement was performed to evaluate body composition. Third, DIO mice were treated with the Y5 antagonist alone, or in combination with 10% food restriction, or with another anorectic agent, sibutramine at 10 mg/kg, for 1.5 months. Plasma glucose, insulin, and leptin levels, and adipose tissue weights were quantified. Results: The spironolactone Y5 antagonist significantly reduced body weight in C57BL DIO mice, but not in Npy5r −/− DIO mice. The Y5 antagonist produced a fat-selective loss of body weight, and ameliorated obesity-associated insulin resistance in DIO mice. In addition, the Y5 antagonist combined with either food restriction or sibutramine tended to produce greater body weight loss, as compared with single treatment. Discussion: These findings demonstrate that the Y5 receptor is an important mediator of energy homeostasis in rodents.