Biological Activity
Histamine affects homeostatic mechanismsincluding food and water consumptionby acting on central nervous system (CNS) receptors. Presynaptic histamine H3 receptors regulate release of histamine and other neurotransmittersand 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 weightwhereas 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
