A 3D-QSAR study on the structural requirements for binding to CB1 and CB2 cannabinoid receptors

A 3D-QSAR study was carried out on 20 cannabinoids for which the binding af finities (K-i) with respect to CB1 and CB2 receptors, determined in the sam e cell line, were available. For the first time three series of significant ly different chemical structures such as Delta(9)-THC analogues, anandamide s, and indoles were included in a single 3D-QSAR model, to obtain informati on on the interactions of all ligands with both CB1 and CB2 receptors and o n their receptor selectivity. Delta(9)-THC was chosen as the structural tem plate for alignment. The 3D-structure-activity correlation obtained by the GOLPE procedure provided a partial least squares (PLS) model with a very go od predictive ability for the CB1 receptor affinity of all compounds. The m odel allowed us to identify seven different regions in the space that contr ibute to explain the above binding affinities. External validation of the i nterpretation of the 3D-QSAR model was derived from a response-independent procedure such as principal components analysis (PCA). The CB2 receptor mod el evidenced, besides the seven regions found for the CB1 receptor, a new c haracteristic region for the CB2 receptor. Another PCA, using 10 GRID probe s, provided further evidence of receptor selectivity regions. One region op posite to the amidic NH of CB1 selective O585 appears to be responsible for the CB1 selectivity, while an interaction region opposite to the carbonyl of CB2 selective JWH-015 appears to be involved in the CB2 binding selectiv ity.