Open Access Highly Accessed Research article

Quantitative in vitro and in vivo pharmacological profile of CE-178253, a potent and selective cannabinoid type 1 (CB1) Receptor Antagonist

John R Hadcock1*, Philip A Carpino4, Philip A Iredale2, Robert L Dow4, Denise Gautreau1, Lucinda Thiede1, Dawn Kelly-Sullivan1, Jeffrey S Lizano1, Xingrong Liu5, Jeffrey Van Deusen3, Karen M Ward2, Rebecca E O'Connor2, Shawn C Black6, David A Griffith4 and Dennis O Scott3

Author Affiliations

1 Department of Cardiovascular, Metabolic and Endocrine Diseases, Pfizer Global Research and Development, Groton, CT 06340, USA

2 Department of Neuroscience, Pfizer Global Research and Development, Groton, CT 06340, USA

3 Pharmacokinetics, Dynamics, and Metabolism, Pfizer Global Research and Development, Groton, CT 06340, USA

4 Medicinal Chemistry, Pfizer Global Research and Development, Groton, CT 06340, USA

5 Roche, 3431 Hillview Avenue S3-2, Palo Alto, CA 94304, USA

6 Johnson & Johnson Pharmaceutical Research & Development, Welsh & McKean Roads, Spring House, PA 19477-0776, USA

For all author emails, please log on.

BMC Pharmacology 2010, 10:9  doi:10.1186/1471-2210-10-9

Published: 16 August 2010



Cannabinoid 1 (CB1) receptor antagonists exhibit pharmacological properties favorable for the treatment of obesity and other related metabolic disorders. CE-178253 (1-[7-(2-Chlorophenyl)-8-(4-chlorophenyl)-2-methylpyrazolo[1,5-a]-[1,3,5]triazin-4-yl]-3-ethylaminoazetidine-3-carboxylic acid hydrochloride) is a recently discovered selective centrally-acting CB1 receptor antagonist. Despite a large body of knowledge on cannabinoid receptor antagonists little data exist on the quantitative pharmacology of this therapeutic class of drugs. The purpose of the current studies was to evaluate the quantitative pharmacology and concentration/effect relationships of CE-178253 based on unbound plasma concentration and in vitro pharmacology data in different in vivo preclinical models of FI and energy expenditure.


In vitro, CE-178253 exhibits sub-nanomolar potency at human CB1 receptors in both binding (Ki = 0.33 nM) and functional assays (Ki = 0.07 nM). CE-178253 has low affinity (Ki > 10,000 nM) for human CB2 receptors. In vivo, CE-178253 exhibits concentration-dependent anorectic activity in both fast-induced re-feeding and spontaneous nocturnal feeding FI models. As measured by indirect calorimetry, CE-178253 acutely stimulates energy expenditure by greater than 30% in rats and shifts substrate oxidation from carbohydrate to fat as indicated by a decrease the respiratory quotient from 0.85 to 0.75. Determination of the concentration-effect relationships and ex vivo receptor occupancy in efficacy models of energy intake and expenditure suggest that a greater than a 2-fold coverage of the Ki (50-75% receptor occupancy) is required for maximum efficacy. Finally, in two preclinical models of obesity, CE-178253 dose-dependently promotes weight loss in diet-induced obese rats and mice.


We have combined quantitative pharmacology and ex vivo CB1 receptor occupancy data to assess concentration/effect relationships in food intake, energy expenditure and weight loss studies. Quantitative pharmacology studies provide a strong a foundation for establishing and improving confidence in mechanism as well as aiding in the progression of compounds from preclinical pharmacology to clinical development.