Zaleplon was introduced in Sweden and Denmark as a new treatment
for insomnia, particularly in patients who have difficulty in falling asleep.
Zaleplon is a non-benzodiazepine compound and is the first in a new generation
belonging to the pyrazolopyrimidine class, showing therefore fewer
benzodiazepine-like side effects. It can be synthesized in 3 steps from the
corresponding acetophenone, the key step being the cyclization of the
appropriate enaminone with 3-aminopyrazole-4-carbonitrile. Biochemically,
Zaleplon is a full agonist at the benzodiazepine o)1 site of the gaba-A receptor
complex, but its behavioural profile remains distinct from both benzodiazepine
(e.g. Lorazepam) or non-benzodiazepine (e.g. Zopiclone or Zolpidem) sedativehypnotic
drugs. Clinical pharmacokinetic analysis showed rapid absorption and
elimination. In man, the main metabolic route was oxidative giving the major
metabolites 5-oxo Zaleplon and its N-desethyl analog. Both were shown to have
no effect at central benzodiazepine receptors and to be rapidly excreted as
glucuronides. In patients with chronic insomnia, Zaleplon at 5 and 10 mg/kg
significantly reduced sleep latency and improved the quality of sleep compared
with placebo without altering the normal sleep architecture. Given its short halflife,
the next-day residual effects such as hangover are minimized. It may have
some advantages over benzodiazepines regarding unwanted amnesic effects
and psychomotor impairment. There was no evidence for the occurrence of
rebound insomnia at 10 mg/kg.
Zaleplon (Item No. 11577) is an analytical reference material that is functionally categorized as a sedative. It is a pyrazolopyrimidine that selectively activates the GABAA α1 receptor subunit (EC50 = 1.1 μM), producing a sedative effect. It is characterized as being an ultra-short-acting sedative due to short Tmax (0.7-1.4 hours) and half-life (1 hour) values. This product is intended for research and forensic applications.
American Home Products (US)
topical antibacterial (topical)
Selective non-benzodiazepine GABAA receptor agonist
ChEBI: A pyrazolo[1,5-a]pyrimidine having a nitrile group at position 3 and a 3-(N-ethylacetamido)phenyl substituent at the 7-position.
N-[3-[3-(Dimethylamino)-1-oxo-2-propenyl]phenyl]acetamide amide
A 1 gram-equivalent portion of N-(3-acetylphenyl)ethanamide in equivalent
portion of dimethylformamide dimethyl acetal was refluxed for 8 hours, then
evaporated. The residue was taken up in 200 ml of dichloromethane, passed
through hydrous magnesium silicate, diluted with hexane and concentrated,
giving the desired compound.
N-[3-[3-(Dimethylamino)-1-oxo-2-propenyl]phenyl-N-ethylacetamide
A mixture of 1 gram-equivalent of N-[3-[3-(dimethylamino)-oxo-2-
propenyl]phenyl]propanamide and equivalent portion of 60% sodium hydride
in oil in dimethylformamide was stirred for 0.5 hour under argon, then cooled
in an ice bath and a solution of 1gram-equivalent of ethyl iodide in 10 ml of
dimethylformamide was added in small portions. The mixture was then stirred
at room temperature for 0.5 hour and extracted three times with hexane. The
extracts were discarded, water was added and this mixture extracted with
dichloromethane. This extract was evaporated and the residue crystallized
from hexane giving the desired compound, MP 110°-113°C.
N-[3-(3-Cyanopyrazolo[1,5-a]pyrimidin-7-yl)phenyl]-N-ethylacetamide
A mixture of 1 gram-equivalent of 3-aminopyrazole-4-carbonitrile and 1 gram-
equivalent of N-[3-[3-(dimethylamino)-1-oxo-2-propenyl]phenyl]-N-
ethylacetanamide in 50 ml of glacial acetic acid was refluxed for 8 hours and
then the solvent was removed. The residue was partitioned between saturated
aqueous sodium bicarbonate and dichloromethane. The organic layer was
separated, dried, passed through a pad of hydrous magnesium silicate and
hexane was added to the refluxing filtrate. The mixture was then cooled and
the solid collected, giving the desired product, MP 186°-187°C.
Zaleplon (Sonata, a pyrazolopyrimidine) isanother short-acting nonbenzodiazepine hypnotic.Pharmacologically and pharmacokinetically, zaleplon is similarto zolpidem; both are hypnotic agents with short halflives.It also has selective high affinity for α1-subunit containingBzRs but produces effects at other BzR/GABAAsubtypes as well. Zaleplon is well absorbed following oraladministration with an absolute bioavailability of approximately30% because of significant presystemic metabolism.It exhibits a mean half-life of approximately 1 hour, with lessthan 1% of the dose excreted unchanged in urine. It is primarilymetabolized by aldehyde oxidase to 5-oxo-zaleplon andis also metabolized to a lesser extent by CYP3A4. Ndemethylationyields desethylzaleplon, which is quickly converted,presumably by aldehyde oxidase, to 5-oxo-desethylzaleplon.These oxidative metabolites are thenconverted to glucuronides and eliminated in urine. All of zaleplon’smetabolites are pharmacologically inactive. It mayhave a more rapid onset (about 1 hour) and termination of actionthan zolpidem, and therefore, it is good to initiate sleepinstead of keeping sleep.
Non-benzodiazepine agent that acts as an agonist at the benzodiazepine site. Displays hypnotic, anxiolytic, myorelaxant and anticonvulsant activity.
Zaleplon displays a unique binding profile with GABAA that is distinct from the benzodiazepines but similar to
that of zolpidem. Because of it greater potency for GABAA, the starting dose for zaleplon is comparable to
that of zolpidem. It is rapidly absorbed, with a log P of 1.23, although only 30% of the dose is bioavailable
because of rapid first-pass metabolism via liver cytosolic aldehyde oxidase/xanthine oxidase (molybdenum
hydroxylases) to its major ring oxidation product, 5-oxo-zaleplon metabolite. The minor
metabolism pathways include N-dealkylation from microsomal oxidation via CYP3A4 to N-desethyl-zaleplon and
N-desethyl-5-oxo-zaleplon. It is rapidly metabolized by the liver, with an elimination half-life of approximately 1
hour. The oxidative metabolites are inactive, conjugated with glucuronic acid, and eliminated in the urine.
Inhibitors of CYP3A4 and aldehyde oxidase can increase the plasma concentration of zaleplon significantly,
although this usually does not require dosage modification. Zaleplon does not accumulate with once-daily
administration and displays linear pharmacokinetics in the therapeutic range.
The elimination half-life of
zaleplon is increased in patients with hepatic insufficiency, requiring an adjustment in dosage. High-fat meals
increase the time to peak concentration and decrease the plasma concentration without affecting the half-life.
These results suggest that for faster sleep onset, zaleplon should not be administered either with or
immediately after a meal, which increases the time to reach peak plasma concentrations. In short-term studies
(2–5 weeks), zaleplon has been shown to improve sleep quality with minimal adverse effects and no significant
rebound insomnia on stopping the drug. Because of its short elimination half-life, zaleplon is quite good at
getting people to sleep but is not as good at keeping people asleep. Unlike with zolpidem and eszopiclone, it
has been proposed that if the patient awakens in the middle of the night (with ≥4 hours of sleep time
remaining), another dose of zaleplon can be taken.
