title: Disconnection between the early onset anorectic effects by C75 and hypothalamic fatty acid synthase inhibition in rodents.
abstract: In order to explore the relationship between the anorectic effect of 3-carboxy-4-octyl-2-methylenebutyrolactone (C75) and its pharmacokinetic properties, studies of in vivo and in vitro pharmacological characterization of C75 were performed in Fischer rats. In a quantitative measurement of food intake, we determined that appetite suppression by C75 takes place within 4 h. The C(max) for C75 of 2.6+/-1.5 microM was reached within 1-4 h after intraperitoneal administration at 30 mg/kg, a drug level that causes complete blockade of food intake. However, this concentration is substantially lower than the effective concentration used to inhibit rat fatty acid synthase enzyme activity in vitro (IC50: approximately 200 microM) and hypothalamic enzyme activity was found not to be inhibited by intraperitoneal administration of C75 at 30 mg/kg. Instead, a dramatic induction of c-Fos expression was found in area postrema. Collectively, these data indicate that the anorectic effect of C75 is independent of its inhibition of fatty acid synthase in the hypothalamus.
authors.affiliation: Pharmaceutical Research Institute, Department of Metabolic Disease, Bristol-Myers Squibb Company, Princeton, NJ 08543, USA.
authors.forename: Kenneth W
authors.initials: KW
authors.lastname: Rohrbach
authors.forename: Songping
authors.initials: S
authors.lastname: Han
authors.forename: Jinping
authors.initials: J
authors.lastname: Gan
authors.forename: Eva J
authors.initials: EJ
authors.lastname: O'Tanyi
authors.forename: Hongwei
authors.initials: H
authors.lastname: Zhang
authors.forename: Cecilia L
authors.initials: CL
authors.lastname: Chi
authors.forename: Rebecca
authors.initials: R
authors.lastname: Taub
authors.forename: Brian L
authors.initials: BL
authors.lastname: Largent
authors.forename: Dong
authors.initials: D
authors.lastname: Cheng
mesh_terms: D015107:4-Butyrolactone / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D000818:Animals; D001067:Appetite Depressants / Q000493:pharmacokinetics / Q000494:pharmacology; D001522:Behavior, Animal / Q000187:drug effects; D015152:Blotting, Northern; D003503:Cyclobutanes / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D064429:Fatty Acid Synthases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D005277:Fenfluramine / Q000494:pharmacology; D005508:Food Deprivation; D007031:Hypothalamus / Q000187:drug effects* / Q000201:enzymology; D015151:Immunoblotting; D007274:Injections, Intraperitoneal; D007276:Injections, Intraventricular; D007700:Kinetics; D008297:Male; D010645:Phentermine / Q000494:pharmacology; D012313:RNA / Q000235:genetics / Q000378:metabolism; D011897:Random Allocation; D051381:Rats; D011916:Rats, Inbred F344; D013997:Time Factors
chemical_list: C406734:4-methylene-2-octyl-5-oxofuran-3-carboxylic acid; D001067:Appetite Depressants; D003503:Cyclobutanes; D005277:Fenfluramine; D012313:RNA; D010645:Phentermine; D064429:Fatty Acid Synthases; D015107:4-Butyrolactone; C058254:sibutramine