Molecular requirement for anticonvulsant activity in a series of thiazolo-1,4-benzodiazepine derivatives and comparison with classical benzodiazepines

• 1.1. The behavioural and anticonvulsant effects of several thiazolo[3,2-d][1,4]benzodiazepines (TBZ) were studied after intraperitoneal administration in DBA/2 mice, a strain genetically susceptible to sound-induced seizures.
• 2.2. Anticonvulsant effects on seizures evoked by means of auditory stimulation (109 dB, 12–16 kHz) were evaluated in DBA/2 mice placed singly under a perspex dome.
• 3.3. Hypothermic activity was observed after the highest doses of the benzodiazepines studied.
• 4.4. In addition, some TBZ were examined for anticonvulsant properties with respect to clonus induced by pentylenetetrazol.
• 5.5. Our study demonstrated that some thiazolobenzodiazepine derivatives were more potent than clobazam, desmethylclobazam and chlordiazepoxide, and less potent than diazepam, desmethyldiazepam and alprazolam.
• 6.6. In the series of tricyclic benzodiazepines, thiazole nucleus fusion to the “d” edge of the 7-membered ring results in an effective increase of the energy barrier for the heptatomic system reversal, and is probably responsible for, jointly with the lack of C=N double bonds, lower activity with respect to the 1,4-benzodiazepine precursors.
• 7.7. The potency of various thiazolobenzodiazepine derivatives as inhibitors of specific [³H]flunitrazepam binding to membranes from cerebellum or hippocampus was evaluated.
• 8.8. All tested compounds produced concentration-dependent inhibition of [³H]flunitrazepam binding.
• 9.9. The pharmacological activity of TBZ2, the most active compound of this series, was significantly reduced by treatment with flumazenil (2.5 mg/kg i.p.), suggesting clear involvement of a benzodiazepine mechanism in the anticonvulsant activity of these compounds.