ABSTRACT
Here we describe the characteristics of the cannabinoid receptor subtypes, CB1 and CB2, and what we know of their interactions with certain ligands. CB1 and CB2 are members of the superfamily of 7 transmembrane domain (7TM) receptors that transduce intracellular signals via heterotrimeric GTP-binding proteins. Like many other 7TM receptors the cannabinoid receptors have been the subject of intense research with a view to designing highly specific and potent ligands that may turn out to be effective medicaments for alleviating human ailments. A detailed knowledge of the structure of both ligand and receptor and how they interact may be useful in this respect. Although the two human receptors share only 44% overall identity, ranging from 35% to 82% in the TM regions, it is only recently that subtype specific agonists have been found, those hitherto available showing no or little subtype selectivity. In contrast, two highly specific antagonists, SR 141716A for the CB1 receptor and SR 144528 for the CB2 receptor, besides being promising drug candidates, are also proving to be excellent tools for investigating the structural and functional characteristics of the cannabinoid receptors. We describe experiments with mutated receptors undertaken to try to discover which amino acid residues contact ligands. We also consider the constitutive activity of CB1 and CB2 when they are overexpressed in heterologous systems and the classical inverse agonist properties exhibited by SR 141716A and SR 144528 with their respective target receptors.
Key Words: structure, mutagenesis, ligand-receptor interactions, inverse agonism
