title: The acyclic CB1R inverse agonist taranabant mediates weight loss by increasing energy expenditure and decreasing caloric intake.
abstract: Cannabinoid 1 receptor (CB1R) inverse agonists are emerging as a potential obesity therapy. However, the physiological mechanisms by which these agents modulate human energy balance are incompletely elucidated. Here, we describe a comprehensive clinical research study of taranabant, a structurally novel acyclic CB1R inverse agonist. Positron emission tomography imaging using the selective CB1R tracer [(18)F]MK-9470 confirmed central nervous system receptor occupancy levels ( approximately 10%-40%) associated with energy balance/weight-loss effects in animals. In a 12-week weight-loss study, taranabant induced statistically significant weight loss compared to placebo in obese subjects over the entire range of evaluated doses (0.5, 2, 4, and 6 mg once per day) (p < 0.001). Taranabant treatment was associated with dose-related increased incidence of clinical adverse events, including mild to moderate gastrointestinal and psychiatric effects. Mechanism-of-action studies suggest that engagement of the CB1R by taranabant leads to weight loss by reducing food intake and increasing energy expenditure and fat oxidation.
authors.affiliation: Merck Research Laboratories, Boston, MA 02115, USA.
authors.forename: Carol
authors.initials: C
authors.lastname: Addy
authors.forename: Hamish
authors.initials: H
authors.lastname: Wright
authors.forename: Koen
authors.initials: K
authors.lastname: Van Laere
authors.forename: Ira
authors.initials: I
authors.lastname: Gantz
authors.forename: Ngozi
authors.initials: N
authors.lastname: Erondu
authors.forename: Bret J
authors.initials: BJ
authors.lastname: Musser
authors.forename: Kaifeng
authors.initials: K
authors.lastname: Lu
authors.forename: Jinyu
authors.initials: J
authors.lastname: Yuan
authors.forename: Sandra M
authors.initials: SM
authors.lastname: Sanabria-Bohórquez
authors.forename: Aubrey
authors.initials: A
authors.lastname: Stoch
authors.forename: Cathy
authors.initials: C
authors.lastname: Stevens
authors.forename: Tung M
authors.initials: TM
authors.lastname: Fong
authors.forename: Inge
authors.initials: I
authors.lastname: De Lepeleire
authors.forename: Caroline
authors.initials: C
authors.lastname: Cilissen
authors.forename: Josee
authors.initials: J
authors.lastname: Cote
authors.forename: Kim
authors.initials: K
authors.lastname: Rosko
authors.forename: Isaias N
authors.initials: IN
authors.lastname: Gendrano
authors.forename: Allison Martin
authors.initials: AM
authors.lastname: Nguyen
authors.forename: Barry
authors.initials: B
authors.lastname: Gumbiner
authors.forename: Paul
authors.initials: P
authors.lastname: Rothenberg
authors.forename: Jan
authors.initials: J
authors.lastname: de Hoon
authors.forename: Guy
authors.initials: G
authors.lastname: Bormans
authors.forename: Marleen
authors.initials: M
authors.lastname: Depré
authors.forename: Wai-si
authors.initials: WS
authors.lastname: Eng
authors.forename: Eric
authors.initials: E
authors.lastname: Ravussin
authors.forename: Samuel
authors.initials: S
authors.lastname: Klein
authors.forename: John
authors.initials: J
authors.lastname: Blundell
authors.forename: Gary A
authors.initials: GA
authors.lastname: Herman
authors.forename: H Donald
authors.initials: HD
authors.lastname: Burns
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Hargreaves
authors.forename: John
authors.initials: J
authors.lastname: Wagner
authors.forename: Keith
authors.initials: K
authors.lastname: Gottesdiener
authors.forename: John M
authors.initials: JM
authors.lastname: Amatruda
authors.forename: Steven B
authors.initials: SB
authors.lastname: Heymsfield
mesh_terms: D000328:Adult; D000368:Aged; D000577:Amides / Q000494:pharmacology* / Q000627:therapeutic use; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D002149:Energy Intake / Q000187:drug effects*; D004734:Energy Metabolism / Q000187:drug effects*; D005223:Fats / Q000378:metabolism; D006801:Humans; D008875:Middle Aged; D049268:Positron-Emission Tomography; D011725:Pyridines / Q000494:pharmacology* / Q000627:therapeutic use; D043884:Receptor, Cannabinoid, CB1 / Q000819:agonists*; D015431:Weight Loss / Q000187:drug effects*
chemical_list: D000577:Amides; D005223:Fats; D011725:Pyridines; D043884:Receptor, Cannabinoid, CB1; C521311:N-(3-(4-chlorophenyl)-2-(3-cyanophenyl)-1-methylpropyl)-2-methyl-2-((5-(trifluoromethyl)pyridin-2-yl)oxy)propanamide