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The Importance of the Orientation of the C9 Substituent to Cannabinoid Activity (1989)

The Importance of the Orientation of the C9 Substituent to Cannabinoid Activity (1989)

  1. Alfa
    Journal of Medicinal Chemistry 1989 Jul;32(7):1630-5

    Reggio PH (http://www.ncbi.nlm.nih.gov/sites/e...l.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlus), Greer KV (http://www.ncbi.nlm.nih.gov/sites/e...l.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlus), Cox SM (http://www.ncbi.nlm.nih.gov/sites/e...l.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlus).

    We have found a correlation between cannabinoid psychopharmacological activity and the orientation of the C9 substituent in one class of cannabinoid derivatives. We report here a study of the active cannabinoids delta 9-tetra-hydrocannabinol (delta 9-THC), delta 8-tetrahydrocannabinol (delta 8-THC), and 11 beta-hexahydrocannabinol (11 beta-HHC); the minimally active cannabinoid 11 alpha-hexahydrocannabinol (11 alpha-HHC); and the inactive cannabinoids delta 7-tetrahydrocannabinol (delta 7-THC) and delta 9,11-tetrahydrocannabinol (delta 9,11-THC). Our working hypothesis is that there are two components of cannabinoid structure which confer upon these compounds reactivity characteristics crucial to activity: the directionality of the lone pairs of electrons of the phenyl group hydroxyl oxygen and the orientation of the carbocyclic ring relative to this oxygen. The structures of these six molecules were optimized by using the method of molecular mechanics as encoded in the MMP2(85) program. Other possible minimum-energy conformations of the carbocyclic ring were calculated by driving one torsion angle in this ring by use of the dihedral driver option in MMP2(85). The rotational energy behavior of the phenyl group hydroxyl in each molecule was studied also by using the dihedral driver option in MMP2(85). We found that the carbocyclic ring in 11 alpha-HHC can exist in either a chair or a twist conformation. The carbocyclic ring in delta 9-THC, in delta 8-THC, and in delta 7-THC was found to exist only in a half-chair conformation, while the carbocyclic ring in 11 beta-HHC and in delta 9,11-THC was found to exist only in a chair form. The results of the rotational energy profiles indicated that the minimum-energy positions of the phenyl group hydroxyls are nearly identical in all molecules. These molecules, then, were found to differ only in the conformation of the carbocyclic ring in each. This conformation, in turn, determines the orientation of this ring and its C9 substituent relative to the oxygen of the phenyl group hydroxyl. In order to assess the orientation of the carbocyclic ring with respect to the phenyl group hydroxyl oxygen 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).