The acyclic CB1R inverse agonist taranabant mediates weight loss by increasing energy expenditure and decreasing caloric intake.
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.
Addy
Carol
C
Merck Research Laboratories, Boston, MA 02115, USA.
Wright
Hamish
H
Van Laere
Koen
K
Gantz
Ira
I
Erondu
Ngozi
N
Musser
Bret J
BJ
Lu
Kaifeng
K
Yuan
Jinyu
J
Sanabria-Bohórquez
Sandra M
SM
Stoch
Aubrey
A
Stevens
Cathy
C
Fong
Tung M
TM
De Lepeleire
Inge
I
Cilissen
Caroline
C
Cote
Josee
J
Rosko
Kim
K
Gendrano
Isaias N
IN
Nguyen
Allison Martin
AM
Gumbiner
Barry
B
Rothenberg
Paul
P
de Hoon
Jan
J
Bormans
Guy
G
Depré
Marleen
M
Eng
Wai-si
WS
Ravussin
Eric
E
Klein
Samuel
S
Blundell
John
J
Herman
Gary A
GA
Burns
H Donald
HD
Hargreaves
Richard J
RJ
Wagner
John
J
Gottesdiener
Keith
K
Amatruda
John M
JM
Heymsfield
Steven B
SB
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*
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