These results indicate that MEM could be useful for the treatment of ocular diseases, including diabetic retinopathy with neurodegeneration, elevated vitreoretinal VEGF protein levels, and increased BRB breakdown. In addition to the neuroprotective effect of this compound, MEM can reduce vascular changes seen in diabetic retinas. These data are the first to identify the vasculoprotective effect of MEM.

BRI produced marked decreases in vitreoretinal VEGF and inhibition of BRB breakdown in diabetic rats. The mechanism for these effects may involve attenuation of retinal NMDA receptor activity by BRI. The results suggest that BRI would be useful for treatment of ocular diseases associated with BRB leakage, such as diabetic macular edema and retinopathy.

No abstract

A series of 2-(arylamino)imidazoles was synthesized and evaluated for activity at alpha 1- and alpha 2-adrenoceptors. This class of agents has been shown to have potent and selective agonist activity at the alpha 2-adrenoceptors. The most potent member of this class, 2-[(5-methyl-1,4-benzodioxan-6yl)amino]imidazole, proved efficacious for the reduction of intraocular pressure upon topical administration and for the reduction of blood pressure upon intravenous administration. During the course of our studies, we developed a new reagent that allowed rapid assembly of the target compounds. This reagent, N-(2,2-diethoxyethyl)carbodiimide, was convenient to prepare and was stable under low-temperature storage conditions.

Brimonidine is a relatively selective alpha-2 adrenoceptor agonist that is being developed for the treatment of glaucoma. Because brimonidine is chemically related to clonidine and has affinity for the nonadrenergic imidazoline receptor, its ocular effects may be unrelated to alpha-2 receptor activation. The objective of this study was to determine the pharmacology of the intraocular pressure (IOP) response to brimonidine in rabbits and monkeys and the side effects (miosis, cardiovascular depression) in monkeys. Conscious albino rabbits and cynomolgus monkeys were pretreated topically with the following receptor antagonists: rauwolscine (alpha-2), idazoxan (alpha-2, imidazoline), SKF 105854 (vascular postjunctional alpha-2), and prazosin (alpha-1). Intraocular pressure, pupil size, or blood pressure/heart rate was monitored noninvasively for 6 hours following dosing. Binding experiments were performed using [3H]brimonidine in membrane preparations from rabbit iris/ciliary body and from monkey cerebral cortex and brain stem. In rabbits, the ocular hypotensive response to brimonidine was unilateral and was inhibited by rauwolscine > idazoxan >> SKF 105854 = prazosin; this ranked order of potency correlated with displacement of [3H]brimonidine in the rabbit iris/ciliary body. In monkeys, brimonidine decreased IOP bilaterally and suppressed cardiovascular function suggesting a CNS site of action. Intraocular pressure and cardiovascular responses to brimonidine were inhibited by idazoxan >> rauwolscine > SKF 105854 = prazosin; a similar profile was obtained for displacement of [3H]brimonidine in monkey brain tissue. Both rauwolscine and idazoxan inhibited the miotic response to brimonidine in monkeys. Taken together, these results indicate that brimonidine stimulates an ocular alpha-2 adrenoceptor to decrease IOP in the rabbit and a CNS imidazoline receptor to decrease IOP, blood pressure, and heart rate in the cynomolgus monkey. The miotic response in the monkey is mediated by an alpha-2 adrenoceptor. The alpha-1 and vascular postjunctional alpha-2 adrenoceptors do not appear to play a role in mediating these responses.