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 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.
Hancock
Arthur A
AA
Abbott Laboratories, Global Pharmaceutical Research and Development, 100 Abbott Park Road, Abbott Park, IL 60064-6125, USA. Art.A.Hancock@Abbott.com
Bennani
Youssef L
YL
Bush
Eugene N
EN
Esbenshade
Timothy A
TA
Faghih
Ramin
R
Fox
Gerard B
GB
Jacobson
Peer
P
Knourek-Segel
Victoria
V
Krueger
Kathleen M
KM
Nuss
Merrill E
ME
Pan
Jia Bao
JB
Shapiro
Robin
R
Witte
David G
DG
Yao
Betty B
BB
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
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