CONFORMATIONAL STUDIES ON A DIASTEREOISOMERIC PAIR OF TRICYCLIC NONCLASSICAL CANNABINOIDS BY NMR-SPECTROSCOPY AND COMPUTER MOLECULAR MODELING

Among the nonclassical cannabinoids, CP-55,244 (4), which incorporates an axial 14 beta-hydroxymethyl group, is pharmacologically 30 times m ore potent than its prototype CB-47,497 (2) and 300 times more potent than Delta(9)-THC (1). It has a high degree of stereoselectivity (abou t 120:1) with respect to its diastereoisomer, CP-97,587 (5), which dif fers structurally by having the 14-hydroxymethyl group equatorial. Con formational studies of 4 and 5 were carried out using 2D NMR spectrosc opy and molecular modeling in order to define and compare the similari ties and differences between them. Specific structural features of int erest are the conformation of the 1', 1'-dimethylheptyl (DMH) side cha in, the conformation of the cyclohexyl rings, the orientation of the p henolic ring (A ring) relative to the cyclohexyl ring (C ring), and th e orientation of the hydroxymethyl group as well as the formation of i ntramolecular hydrogen bonding. Our results show that the conformation s of the phenolic hydroxyl (Ph-OH) and DMH side chain for 4 are simila r to those of 2. The proton of the phenolic hydroxyl is pointing away from the C ring while the DMH chain randomly adopts one of four dynami cally averaged conformers in which it is almost perpendicular to the p lane of the aromatic ring. The relative orientation of the A and C rin gs is such that the two rings interconvert between two low-energy conf ormations. Compound 5 prefers the conformer with the Ph-OH pointing to ward the ct-face of the cyclohexyl ring, while for 4, there is an incr eased preference for the conformer where the Ph-OH is directed toward the beta face. This may be due to intramolecular H-bonding between the Ph-OH and the axial 14 beta-hydroxymethyl group of 4 that stabilizes this conformation. Hydrogen bonding between the Ph-OH and the equatori al 14 alpha-hydroxymethyl of 5 was not detected. Thus, the orientation of the aliphatic hydroxyl group with respect to the D ring in 4 and 5 may play an important role with regard to the pharmacophoric requirem ents of the two analogs for the cannabinoid receptor and provide an ex planation for the observed differences in their biological properties.