A theoretical structure-affinity relationship study of some cannabinoid derivatives

A ZINDO/1 quantum-chemical structure-affinity relationship study with the KPG model is presented for the in vitro interaction of a group of classical, indole-derived and aminoalkylindole-derived cannabinoids with CB1 and CB2 receptors. From this work the following conclusions are obtained. CB1 and CB2 CB2 receptor affinities are regulated by different mechanisms involving orbital and charge control. Nevertheless CB1 and CB2 classical ligands share three common features: a hydrogen bond to a lysine (for CB1) or serine (for CB2), a fully aromatic ring and a branched carbon side chain. In the case of indole-derived and aminoalkylindole-derived cannabinoids orientation and alignment rules have been defined as a basis for the comparison of noncongeneric molecules. In this way it was possible to associate the location of molecular fragments of these systems with known molecular systems such as classical cannabinoids. For aminoalkylindoles we have proposed the locus with which they bind to a second receptor site that is available to WIN-55212-2 but not to classical cannabinoids. On the basis of our results we propose a new molecule that should help to discriminate between the above two receptor sites