Cannabinoid CBI receptor antagonists exhibit pharmacologic properties favorable for the treatment of metabolic disease. CP-945,598 (1-[9-(4-chloropheny1)-8-(2-chloropheny1)-9H-purin-6-yl]-4-ethylamino piperidine-4-carboxylic acid amide hydrochloride) is a recently discovered selective, high affinity, competitive CB, receptor antagonist that inhibits both basal and cannabinoid agonist-mediated CBI receptor signaling in vitro and in vivo. CP-945,598 exhibits sub-nanomolar potency at human CBI receptors in both binding (K-i = 0.7 nM) and functional assays (K-i = 0.2 nM). The compound has low affinity (K-i = 7600 nM) for human CB2 receptors. In vivo, CP-945,598 reverses four cannabinoid agonist-mediated CNS-driven responses (hypo-locomotion, hypothermia, analgesia, and catalepsy) to a synthetic cannabinoid receptor agonist. CP-945,598 exhibits dose and concentration-dependent anorectic activity in two models of acute food intake in rodents, fast-induced re-feeding and spontaneous, nocturnal feeding. CP-945,598 also acutely stimulates energy expenditure in rats and decreases the respiratory quotient indicating a metabolic switch to increased fat oxidation. CP-945,598 at 10 mg/kg promoted a 9%, vehicle adjusted weight loss in a 10 day weight loss study in diet-induced obese mice. Concentration/effect relationships combined with ex vivo brain CBI receptor occupancy data were used to evaluate efficacy in behavioral, food intake, and energy expenditure studies. Together, these in vitro, ex vivo, and in vivo data indicate that CP-945,598 is a novel CBI receptor competitive antagonist that may further our understanding of the endocannabinoid system. (C) 2010 Elsevier Inc. All rights reserved.