title: Antiobesity effects of A-331440, a novel non-imidazole histamine H3 receptor antagonist.
abstract: 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 H(3) 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)<==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.
authors.affiliation: Abbott Laboratories, Global Pharmaceutical Research and Development, 100 Abbott Park Road, Abbott Park, IL 60064-6125, USA. Art.A.Hancock@Abbott.com
authors.forename: Arthur A
authors.initials: AA
authors.lastname: Hancock
authors.forename: Youssef L
authors.initials: YL
authors.lastname: Bennani
authors.forename: Eugene N
authors.initials: EN
authors.lastname: Bush
authors.forename: Timothy A
authors.initials: TA
authors.lastname: Esbenshade
authors.forename: Ramin
authors.initials: R
authors.lastname: Faghih
authors.forename: Gerard B
authors.initials: GB
authors.lastname: Fox
authors.forename: Peer
authors.initials: P
authors.lastname: Jacobson
authors.forename: Victoria
authors.initials: V
authors.lastname: Knourek-Segel
authors.forename: Kathleen M
authors.initials: KM
authors.lastname: Krueger
authors.forename: Merrill E
authors.initials: ME
authors.lastname: Nuss
authors.forename: Jia Bao
authors.initials: JB
authors.lastname: Pan
authors.forename: Robin
authors.initials: R
authors.lastname: Shapiro
authors.forename: David G
authors.initials: DG
authors.lastname: Witte
authors.forename: Betty B
authors.initials: BB
authors.lastname: Yao
mesh_terms: D000273:Adipose Tissue / Q000187:drug effects; D000818:Animals; D019440:Anti-Obesity Agents / Q000494:pharmacology*; D001067:Appetite Depressants / Q000494:pharmacology; D001522:Behavior, Animal / Q000187:drug effects; D001713:Biphenyl Compounds / Q000494:pharmacology*; D001823:Body Composition / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D002118:Calcium / Q000378:metabolism; D003001:Cloning, Molecular; D003952:Diagnostic Imaging; D004032:Diet; D004041:Dietary Fats / Q000494:pharmacology; D005277:Fenfluramine / Q000494:pharmacology; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000378:metabolism; D006633:Histamine Antagonists / Q000494:pharmacology*; D006801:Humans; D008279:Magnetic Resonance Imaging; D051379:Mice; D008810:Mice, Inbred C57BL; D009570:Nitriles / Q000494:pharmacology*; D011759:Pyrrolidines / Q000494:pharmacology*; D011869:Radioligand Assay; D051381:Rats; D018100:Receptors, Histamine H3 / Q000187:drug effects*; D015431:Weight Loss / Q000187:drug effects
chemical_list: C493218:4'-(3-(3(R)-(dimethylamino)-pyrrolidin-1-yl)-propoxy)-biphenyl-4-carbonitrile; D019440:Anti-Obesity Agents; D001067:Appetite Depressants; D001713:Biphenyl Compounds; D004041:Dietary Fats; D006633:Histamine Antagonists; D009570:Nitriles; D011759:Pyrrolidines; D018100:Receptors, Histamine H3; D005277:Fenfluramine; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D002118:Calcium