Construction of a steric map of the binding pocket for cannabinoids at the cannabinoid receptor.

In order to gain information about the topology of the brain cannabinoid receptor (CB1), a Receptor Steric (RS) Map for cannabinoids at this receptor was calculated. The classical cannabinoids (-)-11-hydroxy-delta-9-tetrahydrocannabinol (K1 = 210 +/- 56 nM), (-)-9-nor-9-beta-hydroxy-hexahydrocannabinol (K1 = 124 +/- 17 nM), nabilone (K1 = 120 +/- 13 nM), and the non-classical cannabinoid, CP-55,244 (K1 = 1.4 +/- .3 nM) were used as template molecules. The RS map was obtained as the union of the van der Waals' volumes of only those accessible conformers identified by MMP2 calculations that were able to clear a region of steric interference at the CB1 receptor previously characterized by us [Reggio, P.H., Panu, A.M. and Miles, S. (1993), J. Med. Chem., 36, 1761-1771]. The utility of the RS Map was explored by screening the accessible conformers of the classical cannabinoid, cannabinol (CBN), (K1 = 3200 +/- 450 nM), for its ability to fit within the RS map. Only the global minimum energy conformer of CBN (53.2% abundance at 298K) was able to fit within the RS map. These results imply that one reason for the reduced affinity of CBN may be that only 53.2% of CBN molecules are shaped properly to fit in the binding pocket for cannabinoids at the CB1 receptor.