A non-imidazole H3 histamine receptor antagonist. Presynaptic histamine H3 receptors regulate the release of histamine and other neurotransmitters, and histamine H3 receptor antagonists enhance neurotransmitter release. A-331440 is a histamine H3 receptor antagonist, which binds strongly and selectively to both human and rat histamine H(3) receptors (K(i)=25 nM). Mice on a high-fat diet (45 kcal % lard) prior to 28-day oral b.i.d. dosing for measurement of obesity-related parameters. A-331440 administered at 0.5 mg/kg had no significant effect on weight, whereas 5 mg/kg decreased weight comparably to dexfenfluramine (10 mg/kg). A-331440 administered at 15 mg/kg reduced weight to a level comparable to mice on the low-fat diet. The two higher doses reduced body fat and the highest dose also normalized an insulin tolerance test. Both data shows that the histamine H3 receptor antagonist, A-331440, has potential as an antiobesity agent.
