In vivo pharmacological characterization of indiplon, a novel pyrazolopyrimidine sedative-hypnotic.
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.
Foster
Alan C
AC
Department of Neuroscience, Neurocrine Biosciences, 12790 El Camino Real, San Diego, CA 92130, USA. afoster@neurocrine.com
Pelleymounter
Mary Ann
MA
Cullen
Mary Jane
MJ
Lewis
Dacie
D
Joppa
Margaret
M
Chen
Ta Kung
TK
Bozigian
Haig P
HP
Gross
Raymond S
RS
Gogas
Kathleen R
KR
D000818:Animals; D001362:Avoidance Learning / Q000187:drug effects* / Q000502:physiology; D001569:Benzodiazepines / Q000493:pharmacokinetics / Q000494:pharmacology*; D008297:Male; D051379:Mice; D009043:Motor Activity / Q000187:drug effects*; D011597:Psychomotor Performance / Q000187:drug effects* / Q000502:physiology; D051381:Rats; D020318:Rats, Long-Evans; D017207:Rats, Sprague-Dawley; D013876:Thiophenes / Q000493:pharmacokinetics / Q000494:pharmacology*
D013876:Thiophenes; D001569:Benzodiazepines; C469870:indiplon