ABSTRACT
Ligand-based virtual screening led to the discovery of a new class of potent inverse agonists of the human cannabinoid receptor 1, hCB(1), which are selective versus hCB(2). These CB(1) ligands present intriguing departures from a classical CB(1) antagonist pharmacophore. Elements of SAR are discussed in this context.
Subject(s)
Cannabinoids/chemical synthesis , Cannabinoids/pharmacology , Receptor, Cannabinoid, CB1/agonists , Cannabinoids/chemistry , Combinatorial Chemistry Techniques , Drug Design , Humans , Ligands , Molecular Structure , Receptor, Cannabinoid, CB2/agonists , Structure-Activity RelationshipABSTRACT
Database searching led to the identification of potent A(2A) antagonists which do not contain the privileged furan moiety and which show selectivity over A(1) receptors. Simple substructure searching on a proprietary database identified compounds with activities in the low nM range. A targeted approach to the identification of non-furan containing compounds resulted in the identification of two novel series, with potency, selectivity and directional SAR from screening 113 compounds.
Subject(s)
Adenosine A2 Receptor Antagonists , Furans/chemistry , Furans/pharmacology , Amination , Fluorine/chemistry , Furans/chemical synthesis , Furans/metabolism , Models, Molecular , Molecular Structure , Protein Binding , Pyrimidines/chemistry , Pyrimidines/metabolism , Receptor, Adenosine A2A/metabolism , Structure-Activity RelationshipABSTRACT
The cannabinoid CB1 receptor inverse agonist rimonabant induces hypophagia and body weight loss. Reduced body weight may potentially be due to decreased food intake or to direct metabolic effects of drug administration on energy expenditure. This study uses a paired-feeding protocol to quantify the contributions of energy intake to rimonabant-induced body weight loss. Diet-induced obese (DIO) rats were dosed with rimonabant (3, 10 mg/kg PO once daily) and matched with pair-fed controls. Food intake and body weight were measured daily. Blood samples and adipose tissue were collected on day 15 for measurement of plasma adiponectin and adiponectin mRNA levels. DIO rats treated with rimonabant and pair-fed controls showed very similar changes in body weight. Although tolerance developed to the anorectic effect of rimonabant, total food intake was significantly decreased over the 14-day study period and fully accounted for the observed reductions in body weight. Adiponectin mRNA and plasma adiponectin were elevated in vehicle-treated chow-fed animals compared to obese controls, and did not differ between rimonabant-treated and pair-fed animals. The similarities between rimonabant-treated and pair-fed animals in body weight loss and the absence of differences in measures of adiponectin activity between drug-treated and pair-fed animals suggest that the outcomes of this experiment were solely mediated by the drug-induced reduction in food intake.
