Biological Activity
Histamine affects homeostatic mechanisms, including food and water consumption, by acting on central nervous system (CNS) receptors. Presynaptic histamine H3 receptors regulate release of histamine and other neurotransmitters, and histamine H3 receptor antagonists enhance neurotransmitter release. A-331440 [4μ-[3-(3(R)-(dimethylamino)-pyrrolidin-1-yl)-propoxy]-biphenyl-4-carbonitrile] is a histamine H3 receptor antagonist which binds potently and selectively to both human and r at histamine H3 receptors (Ki<=25 nM). Mice were stabilized on a high-f at 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-f at diet. The two higher doses reduced body f at and the highest dose also normalized an insulin tolerance test. These data show th at the histamine H3 receptor antagonist, A-331440, has potential as an antiobesity agent.
