In vivo pharmacological characterization of indiplon,
a novel pyrazolopyrimidine sedative-hypnotic

by
Foster AC, Pelleymounter MA, Cullen MJ, Lewis D, Joppa M,
Chen TK, Bozigian HP, Gross RS, Gogas KR.
Department of Neuroscience,
Neurocrine Biosciences,
12790 El Camino Real,
San Diego, CA 92130, USA.
afoster@neurocrine.com
J Pharmacol Exp Ther. 2004 Nov;311(2):547-59


ABSTRACT

Indiplon (NBI 34060; N-methyl-N-[3-[3-(2-thienylcarbonyl)-pyrazolo[1,5-alpha]pyrimidin-7-yl]phenyl]acetamide), a novel pyrazolopyrimidine and high-affinity allosteric potentiator of GABA(A) receptor function, was profiled for its effects in rodents after oral administration. In mice, indiplon inhibited locomotor activity (ED(50) = 2.7 mg/kg p.o.) at doses lower than the nonbenzodiazepine hypnotics zolpidem (ED(50) = 6.1 mg/kg p.o.) and zaleplon (ED(50) = 24.6 mg/kg p.o.), a sedative effect that was reversed by the benzodiazepine site antagonist flumazenil. Indiplon inhibited retention in the mouse passive avoidance paradigm over a dose range and with a temporal profile that coincided with its sedative activity. Indiplon, zolpidem, and zaleplon were equally effective in inhibiting locomotor activity in the rat and produced dose-related deficits on the rotarod. In a rat vigilance paradigm, indiplon, zolpidem, and zaleplon produced performance deficits over a dose range consistent with their sedative effects, although indiplon alone showed no significant increase in response latency. Indiplon produced a small deficit in the delayed nonmatch to sample paradigm at a dose where sedative effects became apparent. Indiplon was active in the rat Vogel test of anxiety, but it showed only a sedative profile in the mouse open field test. The pharmacokinetic profile of indiplon in both rat and mouse was consistent with its pharmacodynamic properties and indicated a rapid T(max), short t(1/2), and excellent blood-brain barrier penetration. Therefore, indiplon has the in vivo profile of an efficacious sedative-hypnotic, in agreement with its in vitro receptor pharmacology as a high-affinity allosteric potentiator of GABA(A) receptor function, with selectivity for alpha1 subunit-containing GABA(A) receptors.
Indiplon
Sedatives
Gaboxadol
L-838,417
Eszopiclone
Benzo choices
Anticonvulsants
GABAergic drugs
Benzodiazepines
Indiplon : structure
Neuroactive steroids
GABA(A) and fluoxetine
Anxiolytics and antidepressants
GABA, pain and the cerebral cortex
Alpha 1 and alpha 2 GABA(A) receptor subunits
The alpha 2/alpha 3-subtypes of GABA(A) receptor


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