Soft cannabinoid analogues as potential anti-glaucoma agents.

Cannabinoids are able to reduce elevated intraocular pressure; however, their use in glaucoma treatment is not approved due to severe systemic side effects. New cannabinoid derivatives have been designed based on a retrometabolic/soft drug approach; they were expected to have local effect, but not systemic side effects. Lead compounds and soft analogues were prepared using Pechmann condensation. In agreement with the SAR hypothesis used for the present soft drug design, all the compounds that were successfully synthesized had IOP lowering effect, but the common metabolite of soft analogues that was found to be inactive. Accordingly, when the soft analogue 8 was administered i.v., its biological effect lasted just for 15 minutes; nevertheless, when administered topically, its effect lasted significantly longer. Its metabolite, though, was inactive when applied either i.v. or topically. Thus, the designed soft analogues proved to be good candidates for topical control of glaucoma without producing systemic side effects. The preliminary i.v. experimental data could be successfully described by an indirect response PK/PD model.