Long-term studies on anticonvulsant tolerance and withdrawal characteristics of benzodiazepine receptor ligands in different seizure models in mice. II. The novel imidazoquinazolines NNC 14-0185 and NNC 14-0189.
We have reported recently that seizure model and experimental protocol may influence the anticonvulsant tolerance and the withdrawal characteristics of benzodiazepine (BDZ) receptor ligands so that predictions on tolerance and dependence liability of novel drugs should be based on a battery of chronic experiments. In the present study, we evaluated two novel BDZ receptor ligands, i.e., NNC 14-0185 ¿3-(3-cyclopropyl-5-isoxazolyl)-6-fluoro-5-morpholino-imidazo [1,5-a]quinazoline¿ and NNC 14-0189 ¿3-(5-cyclopropyl-1, 2,4-oxadiazol-3-yl)-7-fluoro-5-(4-methyl-1-piperazinyl)-imidazol[1 , 5-a]quinazoline¿, which seem to act as partial agonists at BDZ receptors, in two seizure models by using different experimental approaches to assess the tolerance and dependence liability. In one approach, mice were chronically treated with either NNC 14-0185 or NNC 14-0189 for 4 weeks at doses which were about equipotent to increase the threshold for myoclonic seizures induced by pentylenetetrazole. Anticonvulsant activity was determined several times during the period of chronic treatment as well as up to 2 weeks after termination of treatment in the same group of animals per drug. The threshold for electroshock-induced tonic seizures was used as a second seizure model in separate groups of mice. In another approach, the drug treatment protocols were the same, but the seizures were induced only twice during the 4-week period of treatment to reduce the number of trials which could lead to "learned" tolerance. In additional groups of mice, the seizure thresholds were only determined before and after the period of treatment to assess whether repeated seizure induction during chronic treatment affect the development of dependence. Only moderate tolerance was seen with the two drugs in the pentylenetetrazole seizure threshold experiments and with NNC 14-0185 in the electroshock-induced tonic seizure threshold experiments, whereas NNC 14-0189 did not lose any activity in the latter model during chronic treatment. There was no indication for a significant involvement of learned tolerance during repeated drug testing. With respect to the withdrawal symptoms, i.e., measures of physical dependence-inducing properties of the two drugs, moderate but significant decreases in the seizure threshold were seen in the withdrawal period. Both in terms of tolerance- and dependence-inducing properties and adverse effects seen during chronic treatment in mice, NNC 14-0185 and NNC 14-0189 seem to offer clear advantages compared to the more traditional BDZ receptor ligands.