The ability of the alpha 2-agonists clonidine, B-HT920 (6-allyl-2-amino-5,6,7,8-tetrohydro-4H-thiazolo-[4,5-d]-azepine) and guanfacine to improve memory in aged monkeys has been related to their affinity to bind at a proposed rauwolscine-insensitive (Ri) subtype of alpha 2-adrenergic receptor, while their hypotensive and sedating effects have been related to affinity at a rauwolscine-sensitive site (Rs) (Arnsten et al., 1988). The present study examined the alpha 2-agonist UK-14304 (5-bromo-6 [2-imidazoline-2-yl amino] quinoxaline) for its binding characteristics in tissue from the brain of the rat and for its behavioral effects in aged monkeys. The drug UK-14304 was found to have slightly higher affinity for the Ri than the Rs site (Ki values of 138 and 245 nM, respectively), but was not as selective as the alpha 2-agonist guanfacine (Ki values of 23 and 340 nM, respectively). Consistent with this binding profile, very small doses of UK-14304 (0.00017-0.17 micrograms/kg) produced a reliable but modest improvement in memory in the aged monkeys (average improvement of 16.7% +/- 2.6% following an optimal dose). No hypotensive or sedating side effects were observed at these small doses. However, hypotension and sedation emerged rapidly when the dose was raised above 1.7 micrograms/kg and at the largest doses tested (50.0-100.0 micrograms/kg), hypotension was severe (systolic pressure below 70 mm Hg) and the animals were too sedated to complete cognitive testing. The separation between doses that improved memory and those that produced hypotension and sedation was not as great for UK-14304 as it was for guanfacine, consistent with the greater selectivity of guanfacine for the Ri site. These results offer a fourth example whereby the ability of an alpha 2-agonist to improve cognitive function, without side effects, could be related to the relative affinities for the Ri and Rs sites.