Soft cannabinoid analogues as potential anti-glaucoma agents.

摘要

Cannabinoids are able to reduce elevated intraocular pressure, which is the only controllable major risk factor of open angle glaucoma. The use of cannabinoids, however, in glaucoma treatment is not approved due to their CNS and cardiovascular side effects. Soft drug design might provide a viable solution for the development of a safe anti-glaucoma drug with topical but no systemic effect. Therefore, the aim of this work was to develop a new cannabinoid analogue using the inactive metabolite and soft analogue approaches.; A series of soft cannabinoid analogues was designed and synthesized based on the inactive metabolite and soft analogue approach for possible topical use. The softness of these analogues, that is, the ease of their metabolic degradation, was tested in different biological media. The rate of inactivation was dependent on structure. In vitro half-lives in rat blood, plasma, and liver were of the order of a few minutes, while in human blood they were between 2 and 16 hours. The pharmacokinetic profiles of one of the soft cannabinoid analogues and that of the common metabolite were evaluated in rats and rabbits as well. The noncompartmental analysis revealed short half-lives and, correspondingly, rapid eliminations. Both compounds were distributed according to a two-compartment model. The results of noncompartmental and compartmental analysis indicated some nonlinearity. Nonetheless, even at the highest doses, elimination half-lives were short enough to ensure rapid inactivation in the systemic circulation. The nonlinearity observed could be modeled reasonably well with a single model if a metabolite concentration dependent term was incorporated in the corresponding differential equations. The pharmacodynamic result obtained following i.v. administration of the tested soft analogue was typical for a soft drug that is active and rapidly inactivated. A strong IOP-lowering effect was observed already at the first observation point (3 min) that was parallel in both eyes and lasted 15 minutes. When applied topically, the intraocular pressure lowering effect of these soft drugs was less pronounced but lasted longer. The metabolite, however, showed essentially no activity when administered either locally or systematically, as expected based on the design principles. Thus, all experimental results confirm that the structural modification made according to the rationale of soft drug design maintain activity and ensure predictable metabolism leading to the possibility of development of a safe soft cannabinoid analog with IOP lowering activity.