A rational search for the separation of psychoactivity and analgesia in cannabinoids

The compound 9-beta-hydroxy-hexahydrocannabinol [(−)-9 β-OH-HHC] was designed to fit a combined theoretical profile of an analgesic cannabinoid (equatorial alcohol at C-9, phenol at C-1 and a C-3 side chain) with reduced psychoactivity (axial C-9 substituent which protrudes into the α face). (−)-9 β...

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Veröffentlicht in:Pharmacology, biochemistry and behavior biochemistry and behavior, 1991-11, Vol.40 (3), p.479-486
Hauptverfasser: Reggio, P.H., McGaughey, G.B., Odear, D.F., Seltzman, H.H., Compton, D.R., Martin, B.R.
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Sprache:eng
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Zusammenfassung:The compound 9-beta-hydroxy-hexahydrocannabinol [(−)-9 β-OH-HHC] was designed to fit a combined theoretical profile of an analgesic cannabinoid (equatorial alcohol at C-9, phenol at C-1 and a C-3 side chain) with reduced psychoactivity (axial C-9 substituent which protrudes into the α face). (−)-9 β-OH-HHC was synthesized by the addition of methyl Grignard to 9-oxo-11-nor-HHC. Its α epimer was obtained by the regiospecific epoxide ring opening of 9α, 10 α-epoxy-HHC acetate. (−)-9 β-OH-HHC and (−)-9 α-OH-HHC were each evaluated in a battery of tests in mice and were found to be 10–25 times less potent than (−)-trans- Δ 9-tetrahydrocannabinol ( Δ 9-THC) in all tests including the tail flick test for antinociception (analgesia). Molecular mechanics calculations [MMP2(85)] revealed that, in the global minimum energy conformation of (−)-9 β-OH-HHC, the axial methyl at C-9 protrudes into the α face of the molecule, while the axial hydroxyl at C-9 in (−)-9 α-OH-HHC protrudes into this same face. These calculations also identified a higher energy carbocyclic ring ( twist) conformer of each in which there is no protrusion of a C-9 substituent of the carbocyclic ring into the α face. The minimal activity of both compounds is attributed to these higher energy forms. It is concluded that protrusion of a C-9 substituent into the α-face of the molecule is associated with reduced cannabinoid analgesia, as well as with reduced cannabinoid psychopharmacological activity.
ISSN:0091-3057
1873-5177
DOI:10.1016/0091-3057(91)90350-B