THE CONFORMATIONAL PROPERTIES OF THE HIGHLY SELECTIVE CANNABINOID RECEPTOR-LIGAND CP-55,940

During a search for novel drugs possessing analgesic properties but de void of the psychotropic effects of marijuana, a group of molecules de signated as nonclassical cannabinoids was synthesized by Pfizer. Of th ese non classical cannabinoids CP-55,940 has received the most attenti on principally because it was used as the high affinity radioligand du ring the discovery and characterization of the G-protein-coupled canna binoid receptor. In an effort to obtain information on the stereoelect ronic requirements at the cannabinoid receptor active site, me have st udied the conformational properties of CP-55,940 using a combination o f solution NMR and computer modeling methods. Our data show that for t he most energetically favored conformation, (i) the aromatic phenol ri ng is perpendicular to the cyclohexane ring, and the phenolic O-H bond is coplanar with the aromatic ring and points away from the cyclohexy l ring; ii) the dimethylheptyl chain adopts one of four preferred conf ormations in all of which the chain is almost perpendicular to the phe nol ring; and iii) an intramolecular H-bond between the phenolic and h ydroxypropyl groups allows all three hydroxyl groups of CP-55,940 to b e oriented toward the upper face of the molecule. Such an orientation by the OH groups may be a characteristic requirement for cannabimimeti c activity.