Antiobesity effects of A-331440, a novel non-imidazole histamine H3 receptor antagonist

Histamine affects homeostatic mechanisms, including food and water consumption, by acting on central nervous system (CNS) receptors. Presynaptic histamine H-3 receptors regulate release of histamine and other neurotransmitters, and histamine H3 receptor antagonists enhance neurotransmitter release. A-331440 {4'-[3-(3(R)-(dimethylamino)-pyrrolidin-1-yl)-propoxy]-biphenyl-4-carbonitrile} is a histamine H-3 receptor antagonist which binds potently and selectively to both human and rat histamine H-3 receptors (K-i less than or equal to 25 nM). Mice were stabilized 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. These data show that the histamine H-3 receptor antagonist, A-331440, has potential as an antiobesity agent. (C) 2004 Elsevier B.V. All rights reserved.