Analysis of the anorectic efficacy of HMR1426 in rodents and its effects on gastric emptying in rats

OBJECTIVES: Pharmacodynamics of HMR1426 in rodents. SUBJECTS: Male and female rats and male mice. MEASUREMENTS: 24 h feed consumption was measured. From the time curves IC50 values of HMR1426 were calculated. Microanalysis of feeding behavior was determined. Macronutrient preference was measured, by offering rats three different diets. Gastric emptying was measured after liquid gastric loads or solid meals. In rats with gastric cannulas, milk consumption was measured with closed or open cannulas. Diabetes-related parameters and thyroid hormones were measured. RESULTS: HMR1426 inhibited feed consumption dose-dependently in rodents. Microstructural analysis of feeding after HMR1426 differed from central acting anorectics. HMR1426 inhibited consumption of fat- and carbohydrate-enriched diets. Gastric empyting was dose- and time-dependently delayed. Gastric emptying correlated with the time course of the anorectic effect. In sham-fed rats, HMR1426 had no anorectic effect with open cannulas. Anorectic effect occurred with closed cannulas. We proved that HMR1426 is not a CCKA agonist. CONCLUSION: The correlation between anorectic properties of HMR1426 and gastric emptying suggests that gastric emptying may cause the anorectic properties of HMR1426. The differences in microstructural feeding behavior between HMR1426 and centrally active anorectics makes it unlikely that HMR1426 acts via the CNS. Evidence for a peripheral mode of action is derived from sham-fed rats with open gastric fistula. When the milk fed was drained, HMR1426 was ineffective. HMR1426 is not a CCKA agonist. The molecular action of HMR1426 causing gastric emptying and its anorectic properties are under investigation.