Various cannabinoids have been tested for activity compared to delta 9-THC in reducing intraocular pressure after intravenous administration in rabbits at 0.1 mg or 1 mg/animal. Comparison of l-delta 9-, delta 8-, 11-OH-delta 9- and 11-OH- delta 8-THC indicates that minor configurational changes have only a small influence on activity with regard to induction of a fall in intraocular pressure, although 11-OH-delta 8-THC has increased activity. 8 alpha-OH-, 8 alpha-diOH- and 8 beta-diOH-delta 9-THC have little or no activity but 8 beta-OH-delta 9-THC is as active as delta 9-THC indicating that the hydroxyl group in the beta-position does not influence activity. Modification of the C5H11 alkyl side chain (3'-OH-delta 9-THC) reduced activity to 20% relative to delta 9-THC. Cannabidiol (CBD), cannabichromene, cannabigerol and olivetol had no activity, but 10-OH-CBD had some activity at 2 mg/animal. Cannabinol (CBN) had about half the activity of delta 9-THC and activity was reduced further with 1'-OH-CBN, indicating that side chain modification reduced activity. Neither delta 9-THC, nor cannabigerol, had any effect on intraocular pressure or total outflow facility in the rhesus monkey, suggesting species differences in ocular responses to cannabinoids. Further studies on modification of these compounds is warranted in order to further delineate the structure-activity relationships.
Further studies have been made with water soluble marihuana-derived material (MDM). Neither adrenergic, cholinergic, aldosterone, dopamine or serotonin antagonism affected the fall in intraocular pressure induced by MDM. Partial blockade was obtained with galactose, glucose, or mannose, but not arabinose, when the latter were given at intravenous concentrations of 1 gm/animal and MDM was given at 25 micrograms animal, suggesting that these sugars may be involved at the active site of the MDM glycoproteins. Dexamethasone was without effect on either intravenous or intravitreal MDM indicating that the MDM effect is not a non-specific response to a protein. A similar plant glycoprotein, larch arabinogalactan, at 200 micrograms/animal was without effect on intraocular pressure. Aqueous humor flow rate was increased 3 hours after MDM administration, a period corresponding to the intraocular pressure increase caused by MDM, and fell to 20% of control values when the fall in intraocular pressure occurred. Blood flow through the iris was increased at both one and six hours after intravenous MDM injection indicating a vasodilation which could contribute to the initial increase in intraocular pressure. Intravitreal injection of MDM in rabbit and rhesus monkey caused a fall in intraocular pressure only after a 24 hour delay: the unilateral response indicated that systemic metabolism was not required for activity and the delay was likely caused by the diffusion time to the ciliary processes from the mid-vitreal injection site. The changes in beta-receptors, adenylate cyclase and carbonic anhydrase in the ciliary processes are minimal indicating a possible vascular mechanism of action of MDM.
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