Antagonistic targeting of the histamine H3 receptor decreases caloric intake in higher mammalian species

The main purpose of this study was to examine the effects of a selective histamine H3 receptor antagonist, NNC 38-1202, on caloric intake in pigs and in rhesus monkeys. The compound was given intragastrically (5 or 15 mg/kg), to normal pigs (n = 7) and subcutaneously (1 or 0.1 mg/kg) to obese rhesus monkeys (n = 9). The energy intake recorded following administration of vehicle to the same animals served as control for the effect of the compound. In addition, rhesus monkey and pig histamine H3 receptors were cloned from hypothalamic tissues and expressed in mammalian cell lines. The in vitro antagonist potencies of NNC 38-1202 at the H3 receptors were determined using a functional GTPγS binding assay.Porcine and human H3 receptors were found to have 93.3% identity at the amino acid level and the close homology between the monkey and human H3 receptors (98.4% identity) was confirmed. The antagonist potencies of NNC 38-1202 at the porcine, monkey and human histamine H3 receptors were high as evidenced by Ki-values being clearly below 20 nM, whereas the Ki-value on the rat H3 receptor was significantly higher (56 ± 6.0 nM). NNC 38-1202, given to pigs in a dose of 15 mg/kg, produced a significant (p < 0.05) reduction (55%) of calorie intake compared with vehicle alone, (132.6 ± 10.0 kcal/kg day versus 59.7 ± 10.2 kcal/kg day). In rhesus monkeys administration of 0.1 and 1 mg/kg decreased (p < 0.05) average calorie intakes by 40 and 75%, respectively.In conclusion, the present study demonstrates that antagonistic targeting of the histamine H3 receptor decreases caloric intake in higher mammalian species.