INHIBITION OF ADENOSINE UPTAKE INTO RAT-BRAIN SYNAPTOSOMES BY THE BENZODIAZEPINES

Benzodiazepines (13) [clonazepam, nitrazepam, lorazepam, diazepam, flunitrazepam, medazepam, flurazepam, bromazepam, chlordiazepoxide, oxazepam, RO-11-6893, RO-11-6896 and RO-5-3636] were tested for their ability to inhibit the uptake of adenosine by rat brain synaptosomes. All of the benzodiazepines were able to inhibit adenosine uptake with IC20 [concentration which causes 20% inhibition] values ranging 5 .times. 10-9 M (clonazepam) to 2.0 .times. 10-5 M (RO 11-6893). Clonazepam, nitrazepam, lorazepam, RO 11-6896, diazepam, flunitrazepam, medazepam and flurazepam were the most potent compounds, having IC20 values < 10-6 M. Adenosine uptake would therefore be appreciably reduced at the levels achieved with therapeutic doses (.apprx. 1 .mu.M for diazepam). The d-steroisomer RO 11-6896 was .apprx. 200 times more active than the l-isomer, RO 11-6893. The high IC50 [median inhibitory concentration] values (10-5 to 10-3 M) indicate that dose response curves for the benzodiazepines are rather shallow. Benzodiazepines apparently exert some of their actions via an enhancement of the extracellular levels of adenosine.