Sedative, memory, and performance effects of hypnotics

Roehrs, Timothy; Merlotti, Lori; Zorick, Frank; Roth, Thomas

doi:10.1007/bf02245054

Cited by 109 publications

(49 citation statements)

References 11 publications

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“…Although effective as hypnotics, benzodiazepines also produce undesirable side effects, such as memory impairment, have durations of action that can lead to drowsiness and functional impairment upon awakening ("next day hangover"), and are associated with dependence and abuse liability (Johnson and Chernik, 1982;Lister, 1985;Roehrs et al, 1994;Woods and Winger, 1995). Consequently, the development of drugs with sedative-hypnotic activity equivalent to the benzodiazepines, but with an improved side effect profile, would be of great benefit in the successful management of insomnia, which itself represents an enormous cost to society (Walsh and Engelhardt, 1999).…”

mentioning

confidence: 42%

In Vivo Pharmacological Characterization of Indiplon, a Novel Pyrazolopyrimidine Sedative-Hypnotic

Foster¹,

Pelleymounter²,

Cullen³

et al. 2004

J Pharmacol Exp Ther

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Indiplon (NBI 34060;-pyrazolo[1,5-␣]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 ϭ 2.7 mg/kg p.o.) at doses lower than the nonbenzodiazepine hypnotics zolpidem (ED 50 ϭ 6.1 mg/kg p.o.) and zaleplon (ED 50 ϭ 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 ␣1 subunit-containing GABA A receptors.

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mentioning

confidence: 42%

In Vivo Pharmacological Characterization of Indiplon, a Novel Pyrazolopyrimidine Sedative-Hypnotic

Foster¹,

Pelleymounter²,

Cullen³

et al. 2004

J Pharmacol Exp Ther

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“…If ␣5 subunitcontaining GABA A receptors played a dominant role in the amnesic effects of benzodiazepine site ligands, then one would expect that zolpidem, which has no measurable affinity for this subtype, would be free of amnesic effects. This is not the case, since clinical studies have reported retrograde amnesia with zolpidem (Roehrs et al, 1994) and animal studies clearly show an effect of zolpidem on passive avoidance in the mouse . It seems reasonable to propose that the amnesic effects of hypnotics are inseparable from the hypnosis they produce, which in the case of zolpidem and possibly all benzodiazepine site ligands is most likely a result of positive allosteric modulation at ␣1 subunitcontaining GABA A receptors and not due to a specific interaction with ␣5 subunit-containing GABA A receptors.…”

mentioning

confidence: 44%

Indiplon Is a High-Affinity Positive Allosteric Modulator with Selectivity for α1 Subunit-Containing GABA_AReceptors

Petroski¹,

Pomeroy²,

Das³

et al. 2006

J Pharmacol Exp Ther

114

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Indiplon (NBI 34060) is a novel pyrazolopyrimidine currently in development for the treatment of insomnia. We have previously shown that indiplon exhibits high-affinity binding to native GABA A receptors from rat brain and acts as a positive allosteric modulator of GABA A receptor currents in cultured rat neurons (Sullivan et al., 2004). In this study, we examined the GABA A receptor ␣ subunit selectivity of indiplon using electrophysiological techniques to record GABA-activated chloride currents from recombinant rodent GABA A receptors expressed in human embryonic kidney 293 cells. Indiplon potentiated the GABA-activated chloride current in recombinant GABA A receptors in a dose-dependent and reversible manner and was approximately 10-fold selective for ␣1 subunit-containing receptors over GABA A receptors containing ␣2, ␣3, or ␣5 subunits. The EC 50 values were 2.6, 24, 60, and 77 nM for ␣1␤2␥2, ␣2␤2␥2, ␣3␤3␥2, and ␣5␤2␥2 receptors, respectively. Indiplon was approximately 10 times more potent than zolpidem and zopiclone and Ͼ100 times more potent than zaleplon. Moreover, indiplon, up to 1 M, did not potentiate GABA A receptors composed of ␣4␤2␥2 and ␣6␤2␥2 subunits. This mechanism of action is proposed to underlie the sedative-hypnotic effects of indiplon in animals and humans.GABA is the major inhibitory neurotransmitter in the mammalian central nervous system (Macdonald and Olsen, 1994). Drugs that enhance inhibitory neurotransmission include benzodiazepines, barbiturates, and general anesthetics and are used therapeutically as sedative-hypnotics, anxiolytics, antiepileptics, muscle relaxants, and anesthetics. These drugs target the GABA A receptor, an ion channel that selectively passes chloride when gated by the binding of GABA. Chloride influx serves to hyperpolarize or stabilize a negative resting membrane potential, making the neuron resistant to excitation.The GABA A receptor is a hetero-oligomeric complex composed of five transmembrane spanning subunits from sixteen different genes, ␣(1-6), ␤(1-3), ␥(1-3), ␦, ⑀, , and (Barnard et al., 1998;Korpi et al., 2002;Whiting, 2003). In most neurons, two ␣ subunits, two ␤ subunits, and one ␥ subunit form the typical GABA A receptor (Chang et al., 1996;Tretter et al., 1997). The ␦, ⑀, , and subunits have some reported selective functions but are not yet fully understood. Theoretically, there are thousands of possible subunit combinations, but a limited number of subtype combinations have been found in native systems with ␣1␤2␥2, ␣2␤3␥2, and ␣3␤3␥2 being the most abundant (Whiting, 2003). The assembly of ␣, ␤, and ␥ subunits is required to produce functional GABA A receptors that exhibit all of the pharmacological properties of native GABA A receptors. Benzodiazepine binding occurs at the interface between ␣ and ␥2 subunits (Wieland et al., 1992). GABA elicits chloride currents in recombinant GABA A receptors composed of only ␣ and ␤ subunits, but these currents are not potentiated by benzodiazepines (Schofield et al., 1987).The diversity of subunits and...

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“…Digit Span: Digit Span is a subtest of the WAIS-N which measures attention and working memory and has been found to be sensitive to sleep-inducing agents (36,48).…”

Section: Day L Lldrsshere)supporting

confidence: 45%

Effect of a Hypocretin/Orexin Antagonist on Neurocognitive Performance

Neylan¹

2013

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Public reporting burden for this collection of information is estimated to average 1 hour per response, including the time for reviewing instructions, searching existing data sources, gathering and maintaining the data needed, and completing and reviewing this collection of information. Send comments regarding this burden estimate or any other aspect of this collection of information, including suggestions for reducing this burden to Department of Defense, Washington Headquarters Services, Directorate for Information Operations and Reports (0704-0188), 1215 Jefferson Davis Highway, Suite 1204, Arlington, VA 22202-4302. Respondents should be aware that notwithstanding any other provision of law, no person shall be subject to any penalty for failing to comply with a collection of information if it does not display a currently valid OMB control number. PLEASE DO NOT RETURN YOUR FORM TO THE ABOVE ADDRESS. REPORT DATE (DD-MM-YYYY) SPONSORING / MONITORING AGENCY NAME(S) AND ADDRESS(ES) SPONSOR/MONITOR'S ACRONYM(S) U.S. Army Medical Research and Materiel Command INTRODUCTIONAn integrated translational study will be conducted to examine the effect of a novel hypocretin/orexin antagonist, almorexant (ALM), compared to a standard hypnotic, zolpidem (ZOL), and placebo (PBO) on neurocognitive performance at peak concentration post dosing. The human study component (Task 1; responsible individual: Thomas Neylan, M.D.) will establish whether ALM is superior to ZOL in relation to neurocognitive side effects. It is hypothesized that healthy human subjects receiving 10mg of zolpidem will show greater impairment in neurocognitive performance compared to subjects receiving 100mg or 200mg doses of almorexant or placebo. Study subjects (n=200) will receive a randomly assigned, onetime dose of the study drug in an inpatient hospital setting. A battery of neurocognitive, objective alertness, and subjective symptom assessments will be administered prior to and following dosing. Assessments to be administered were selected based upon their demonstrated sensitivity to sleep-inducing agents and their military relevance. The animal study component (Tasks 2 -5; responsible individual: Thomas Kilduff, Ph.D.) will compare the neural circuitry that underlies the activity of the abovementioned compounds, their effects on sleep and performance, and the effects of these compounds on biomarkers associated with normal sleep.

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Sedative, memory, and performance effects of hypnotics

Cited by 109 publications

References 11 publications

In Vivo Pharmacological Characterization of Indiplon, a Novel Pyrazolopyrimidine Sedative-Hypnotic

In Vivo Pharmacological Characterization of Indiplon, a Novel Pyrazolopyrimidine Sedative-Hypnotic

Indiplon Is a High-Affinity Positive Allosteric Modulator with Selectivity for α1 Subunit-Containing GABA_AReceptors

Effect of a Hypocretin/Orexin Antagonist on Neurocognitive Performance

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Sedative, memory, and performance effects of hypnotics

Cited by 109 publications

References 11 publications

In Vivo Pharmacological Characterization of Indiplon, a Novel Pyrazolopyrimidine Sedative-Hypnotic

In Vivo Pharmacological Characterization of Indiplon, a Novel Pyrazolopyrimidine Sedative-Hypnotic

Indiplon Is a High-Affinity Positive Allosteric Modulator with Selectivity for α1 Subunit-Containing GABAAReceptors

Effect of a Hypocretin/Orexin Antagonist on Neurocognitive Performance

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Indiplon Is a High-Affinity Positive Allosteric Modulator with Selectivity for α1 Subunit-Containing GABA_AReceptors