Tetrazepam: a benzodiazepine which dissociates sedation from other benzodiazepine activities. I. Psychopharmacological profile in rodents.

In the 1,4-benzodiazepine (BZD) series the nature of the C(5) substituent is critical for activity. In tetrazepam this substituent is a cyclohexenyl ring, in all other clinically effective 1,4-BZD derivatives it is a phenyl ring. The activities of tetrazepam and diazepam, whose chemical structures differ only by the nature of the C(5) substituent, were compared in rodent models which are predictive of anticonvulsant, anxiolytic, muscle relaxant and sedative effects. In mice, tetrazepam and diazepam antagonized pentylenetetrazol (PTZ)-induced seizures, increased novel food consumption, decreased rearing behavior in the Staircase test and impaired performance in the Traction test. The effects of both drugs were abolished by Ro 15-1788. In rats, both drugs antagonized PTZ-induced seizures, released punished responding in an approach-avoidance conflict procedure and blocked the PTZ discriminative cue. In mice and rats, and with both BZDs, maximal activity occurred 15 to 30 min after drug administration. In mice and rats, the overall anxiolytic and muscle relaxant potencies of tetrazepam were one-fourth and one-sixth those of diazepam, respectively. The anticonvulsant potency of tetrazepam varied from one-half (rats) to one-twentieth (mice) that of diazepam. In rats and mice, the sedative potency of tetrazepam (Rotorod test; locomotor activity) was approximately one-sixteenth that of diazepam. Finally, tetrazepam induced a loss of righting reflex in mice, with an ED50 value which was approximately 70-times greater than that of diazepam. It is concluded that replacing the 5-phenyl ring by a 5-cyclohexenyl ring leads to a relative dissociation of the pharmacological actions of the 1,4-BZDs.