A Review of the Preclinical Development of Zaleplon, a Novel Non-Benzodiazepine Hypnotic for the Treatment of Insomnia

Zaleplon (N-[3-(3-cyanopyrazolo[l,5-a]pyrimidin-7-y l)phenyl)]-N-ethylacetamide) is a non-benzodiazepine sedative-hypnotic with benzodiazepine-like sedative effects, but with less apparent liability for accompanying undesirable side effects. Zaleplon displaces [³H]flunitrazepam from rat cortical membranes with an IC₅₀ value of 200 nM and enhances t-butylbicyclophosphorothionate [³⁵S]TBPS binding by 73%, suggesting pharmacological activity mediated by the GABA_A benzodiazepine receptor complex. In various preclinical procedures such as motor activity, muscle relaxation, EEG, anticonvulsant activity, and vigilance, zaleplon produced effects similar to those of other sedative-hypnotic compounds such as triazolam and flurazepam; furthermore, these effects, when evaluated, were reversed by the benzodiazepine receptor antagonist flumazenil. Zaleplon increased punished (conflict) responding in squirrel monkeys and rats and these effects were also antagonized by flumazenil. When established as a discriminative stimulus in rats at 3.0mg/kg i.p., zaleplon showed a dose-related increase in drug-appropriate responding up to the training dose and a correlated decrease in response rate. Triazolam (0.1 to 1.0 mg/kg), the benzodiazepine partial agonist Ro 17-1812 (0.3 to 3.0mg/kg), and the triazolopyridine CL 218,872 (1.0 to 3.0 mg/kg) substituted consistently for zaleplon in all rats, whereas the imidazo-pyridines zolpidem (3.0 to 10 mg/kg) and alpidem (10 to 30 mg/kg), the benzodiazepine partial agonist bretazenil (0.03 to 10 mg/kg) and the novel putative anxio-lytic CL 273,547 (10 to 56 mg/kg) did not result in consistent drug-appropriate responding in all rats. These results suggest that the effects of zaleplon are similar in many respects to other compounds acting at the benzodiazepine receptor complex but differ as well from both benzodiazepine and non- benzodiazepine drugs. This profile of activity, coupled with additional information in ancillary procedures, yields a pre-clinical profile of a short-acting sedative-hypnotic non-benzodiazepine that is currently in Phase III development for the treatment of sleep disturbances.