CONFORMATIONAL-ANALYSIS OF THE PROTOTYPE NONCLASSICAL CANNABINOID CP-47,497, USING 2D NMR AND COMPUTER MOLECULAR MODELING

In an effort to determine the stereochemical requirements for pharmaco logical activity among the series of nonclassical cannabinoids synthes ized at Pfizer, we have studied the conformational properties of the p arent bicyclic analog CP-47,497. For this study, we have used a combin ation of solution NMR and theoretical computational approaches. The en ergetically favored conformation has the phenolic ring almost perpendi cular to the cyclohexanol ring which exists in a chair conformation. T he OH bond of the phenol is preferentially coplanar with the aromatic ring and points toward the C2 ring proton, while the dimethylheptyl si de chain adopts a conformation almost perpendicular to the aromatic ri ng. The conformational features of this nonclassical cannabinoid analo g closely resemble those of its classical counterparts. The only appar ent difference is the small dihedral angle (phi(1) = 62 degrees) betwe en the planes of the two rings of CP-47,497 compared to that of the tr icyclic tetrahydro- or hexahydrocannabinol analogs (phi(1) = 137 degre es). However, CP-47,497 can be perfectly superimposed over the respect ive tricyclic analog by rotation around the Ph-cyclohexyl bond (C6-C7 bond) and assume a conformation which is energetically higher than the preferred one by 3.0 kcal/mol. It can be argued that such a conformat ion may be acquired by the nonclassical analog during its interaction with the active site.