Effect of some potent adenosine uptake inhibitors on benzodiazepine binding in the CNS

A series of nucleoside transport inhibitors has been tested for their ability to displace [(3)H]diazepam binding to CNS membranes. No correlation between their potency as [(3)H]adenosine uptake blockers and as inhibitors of [(3)H]diazepam binding was found, either in rat or guinea-pig brain tissue. Dipyridamole, a potent adenosine transport inhibitor interacted strongly (K(i) = 54 nM) with peripheral-type benzodiazepine binding sites ("acceptor sites") and was 4-5 fold weaker in displacing [(3)H]methylclonazepam and [(3)H]Ro15-1788, ligands selective for the specific central benzodiazepine "receptor". Unlike the benzodiazepines, dipyridamole had no anticonvulsant action against metrazole-induced convulsions in mice. Ro5-4864, a benzodiazepine which selectively interacts with the peripheral-type benzodiazepine binding site, was approximately equipotent with diazepam in inhibiting [(3)H]adenosine uptake in brain tissue. These results do not support the idea of a very close link between high-affinity central binding sites for clinically-active benzodiazepines and the adenosine uptake site. The possibility of a connection between benzodiazepine "acceptor" sites and the membrane nucleoside transporter is discussed.