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.

Factors influencing the potency of UK 14,304 analogs including conformational preorganization and arrangement of hydrogen bond acceptors on the aromatic core are described. The previously reported importance of twist of the iminoimidazoline ring relative to the core for enhanced α2 activity is supported.

Tetrahydroquinoxaline analogs of UK 14,304 were prepared. These agents proved to be highly polar, potent, and selective α2-adrenoceptor agonists. This study suggested that agents bearing a twist of the imidazoline ring relative to the quinoxaline nucleus prove more potent than planar analogs.