A number of compounds have been tested for their abilities to inhibit the rapid uptake of adenosine by rat cerebral cortical synaptosomes. Prostaglandins PGI2, PGA2, and PGE1 and PGE2 were potent inhibitors of adenosine uptake with IC20 values in the 10(-7) M-10(-6) M range. PGA1, PGD2 and PGF2 alpha also inhibited uptake but were less active. The benzodiazepine antagonist Ro 15-1788 inhibited adenosine uptake and failed to antagonize the effects of diazepam. Another antagonist, ethyl-beta-carboline-3-carboxylate, was a weak inhibitor of adenosine uptake. Ro 5-4864, the so-called peripheral benzodiazepine ligand, inhibited adenosine uptake. Hydroxyzine and tracazolate, two anxiolytic agents, inhibited uptake as did flunarizine, a coronary vasodilator. Two calmodulin antagonists, W7 and R 24571, were effective inhibitors of adenosine uptake. Their IC50 values were comparable to those at which they have been demonstrated to inhibit calmodulin-mediated reactions in other systems. These observations suggest that adenosine uptake may be a calmodulin-regulated process.