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 pharmacological activity among the series of nonclassical cannabinoids synthesized at Pfizer, we have studied the conformational properties of the parent bicyclic analog CP-47,497. For this study, we have used a combination of solution NMR and theoretical computational approaches. The energetically favored conformation has the phenolic ring almost perpendicular to the cyclohexanol ring which exists in a chair conformation. The OH bond of the phenol is preferentially coplanar with the aromatic ring and points toward the C2 ring proton, while the dimethylheptyl side chain adopts a conformation almost perpendicular to the aromatic ring. The conformational features of this nonclassical cannabinoid analog closely resemble those of its classical counterparts. The only apparent difference is the small dihedral angle (psi 1 = 62 degrees) between the planes of the two rings of CP-47,497 compared to that of the tricyclic tetrahydro- or hexahydrocannabinol analogs (psi 1 = 137 degrees). However, CP-47,497 can be perfectly superimposed over the respective 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 conformation may be acquired by the nonclassical analog during its interaction with the active site.
Xie
X Q
XQ
Section of Medicinal Chemistry and Pharmacognosy, School of Pharmacy, University of Connecticut, Storrs 06269.
Yang
D P
DP
Melvin
L S
LS
Makriyannis
A
A
D002186:Cannabinoids / Q000737:chemistry*; D003198:Computer Simulation; D003511:Cyclohexanols / Q000737:chemistry*; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D008968:Molecular Conformation
D002186:Cannabinoids; D003511:Cyclohexanols; C036088:CP 47497