Design, synthesis, and binding studies of new potent ligands of cannabinoid receptors

Despite their different chemical structures, Delta(9)-tetrahydrocannabinol (THC) and anandamide (AEA) have common pharmacological properties. This study was aimed at finding new cannabinoid receptor ligands that overcome the instability of AEA and its analogues. To this end we planned the synthesis of a series of compounds which retained both a rigid structure, like that of plant cannabinoids, and a flexible portion similar to that of anandamide. Binding studies on CB1 and CB2 receptors, anandamide membrane transporter (AMT), and fatty acid amide hydrolase (FAAH) showed that some of the newly developed compounds have high affinity and specificity for cannabinoid CB1 and CB2 receptors. Compound 25 is a potent CB1 and CB2 ligand, with affinity constants significantly lower than AEA and similar to WIN 55-212, compound 52 is a potent CB2 ligand, although not very selective over CB1 receptors, and compound 43 is CB2 ligand, with at least a 26-fold selectivity over CB1 receptors. Compound 25 behaved as a inverse agonist at CB1 receptors as assessed in the cyclic AMP functional assay.