3D-QSAR Studies on Cannabinoid CB1 Receptor Agonists: G-Protein Activation as Biological Data

G-protein activation via the CB1 receptor was determined for a group of various CB1 ligands and utilized
as biological activity data in subsequent CoMFA and CoMSIA studies. Both manual techniques and automated
docking at CB1 receptor models were used to obtain a common alignment of endocannabinoid and classical
cannabinoid derivatives. In the final alignment models, the endocannabinoid headgroup occupies a unique
region distinct from the classical cannabinoid structures, supporting the hypothesis that these structurally
diverse molecules overlap only partially within the receptor binding site. Both CoMFA and CoMSIA produce
statistically significant models based on the manual alignment and a docking alignment at one receptor
conformer. Leave-half-out cross-validation and progressive scrambling were successfully used in assessing
the predictivity of the QSAR models.