The Importance of the Orientation of the C9 Substituent to Cannabinoid Activity
Chemistry and Biochemistry
A correlation existed between cannabinoid psychopharmacol. activity and the orientation of the C9 substituent in 1 class of cannabinoid derivs. The active cannabinoids Δ9-tetrahydrocannabinol (Δ9-THC), Δ8-tetrahydrocannabinol (Δ8-THC), and 11β-hexahydrocannabinol (11β-HHC), the minimally active cannabinoid 11α-hexahydrocannabinol (11α-HHC), and the inactive cannabinoids Δ7-tetrahydrocannabinol (Δ7-THC) and Δ9,11-tetrahydrocannabinol (Δ9,11-THC) were studied to det. whether there are 2 components of cannabinoid structure which confer upon these compds. reactivity characteristics crucial to activity: the directionality of the lone pairs of electrons of the Ph group OH O and the orientation of the carbocyclic ring relative to this O. The structures of these 6 mols. were optimized by using the method of mol. mechanics as encoded in the MMP2(85) program. Other possible min.-energy conformations of the carbocyclic ring were calcd. by driving 1 torsion angle in this ring by use of the dihedral driver option in MMP2(85). The rotational energy behavior of the Ph group OH in each mol. was studied also by using the dihedral driver option in MMP2(85). The carbocyclic ring in 11α-HHC could exist in either a chair or a twist conformation. The carbocyclic ring in Δ9-THC, Δ8-THC, and Δ7-THC existed only in a half-chair conformation, while the carbocyclic ring in 11β-HHC and in Δ9,11-THC existed only in a chair form. The results of the rotational energy profiles indicated that the min.-energy positions of the Ph group hydroxyls were nearly identical in all mols. These mols., then, differed only in the conformation of the carbocyclic ring in each. This conformation, in turn, detd. the orientation of this ring and its C9 substituent relative to the O of the Ph group OH. In order to assess the orientation of the carbocyclic ring with respect to the Ph group OH O in each optimized structure, the following nonbonded torsion angles were measured: C10-C10a-C1-O, C8-C7-C1-O, C11-C9-C1-O, and C9-Q-C1-O (where Q is a dummy atom placed midway between C8 and C10). A correlation was found between activity and the C11-C9-C1-O angle, an angle that measures the orientation of the C11 Me group (i.e., the C9 substituent) relative to the O of the Ph group OH. C11-C9-C1-O was neg. for all active cannabinoids. As C11-C9-C1-O becomes pos., activity is significantly reduced or abolished. Thus, there is a crit. area near the top of the carbocyclic ring which must not be blocked. Such findings argue strongly for a steric requirement at the site of action of these compds.
Reggio PH, Greer KV, Cox SM. 1989. The importance of the orientation of the C9 substituent to cannabinoid activity. J Med Chem 32(7):1630-5.