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GABAA receptor occupancy by subtype selective GABAA?2,3 modulators: PET studies in humans.

ABSTRACT: RATIONALE:Sedation, dependence, and abuse liability limit the use of non-selective ?-aminobutyric acid (GABAA) receptor positive modulators for the treatment of anxiety. AZD7325 and AZD6280 are novel, subtype-selective GABAA?2,3 receptor positive modulators with limited sedative effects. OBJECTIVES:The current study aimed to confirm target engagement at GABAA receptors by AZD7325 and AZD6280 in humans and to determine the relationship between exposure, GABAA receptor occupancy, and tolerability. METHOD:Two PET studies, using high-resolution research tomography (HRRT) and the radioligand [11C]flumazenil, were performed in 12 subjects at baseline and after administration of single oral doses of AZD7325 (0.2 to 30 mg) and AZD6280 (5 to 40 mg). PET images were analyzed using a simplified reference tissue model, and regional binding potentials (BPND) were obtained. The relationship between plasma concentration of AZD7325 or AZD6280 and GABAA receptor occupancy was described by hyperbolic function, and K i,plasma (plasma concentration required for 50% receptor occupancy) was estimated. Assessments of safety and tolerability included recording of adverse events, vital signs, electrocardiogram, and laboratory tests. RESULTS:The [11C]flumazenil binding was reduced in a dose-dependent, saturable manner by both agents. Maximum receptor occupancy could be reached for both compounds without causing sedation or cognitive impairment. The K i,plasma estimates for AZD7325 and AZD6280 were 15 and 440 nmol/l, respectively. CONCLUSION:High GABAA receptor occupancy by AZD7325 and AZD6280 could be reached without clear sedative effects.

SUBMITTER: Jucaite A

PROVIDER: S-EPMC5263201 | biostudies-literature | 2017 Feb

REPOSITORIES: biostudies-literature

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GABA<sub>A</sub> receptor occupancy by subtype selective GABA<sub>Aα2,3</sub> modulators: PET studies in humans.

Jucaite Aurelija A Cselényi Zsolt Z Lappalainen Jaakko J McCarthy Dennis J DJ Lee Chi-Ming CM Nyberg Svante S Varnäs Katarina K Stenkrona Per P Halldin Christer C Cross Alan A Farde Lars L

Psychopharmacology 20161224 4

<h4>Rationale</h4>Sedation, dependence, and abuse liability limit the use of non-selective γ-aminobutyric acid (GABA<sub>A</sub>) receptor positive modulators for the treatment of anxiety. AZD7325 and AZD6280 are novel, subtype-selective GABA<sub>Aα2,3</sub> receptor positive modulators with limited sedative effects.<h4>Objectives</h4>The current study aimed to confirm target engagement at GABA<sub>A</sub> receptors by AZD7325 and AZD6280 in humans and to determine the relationship between expos ...[more]

PMID: 28013354

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Project description:BackgroundThe current standard of care for insomnia includes gamma-aminobutyric acid receptor A (GABAA) activators, which promote sleep as well as general central nervous system depression. Dual orexin receptor antagonists (DORAs) represent an alternative mechanism for insomnia treatment that induces somnolence by blocking the wake-promoting effects of orexin neuropeptides. The current study compares the role and interdependence of these two mechanisms on their ability to influence sleep architecture and quantitative electroencephalography (qEEG) spectral profiles across preclinical species.ResultsActive-phase dosing of DORA-22 induced consistent effects on sleep architecture in mice, rats, dogs, and rhesus monkeys; attenuation of active wake was accompanied by increases in both non-rapid eye movement (NREM) and rapid eye movement (REM) sleep. Eszopiclone, a representative GABAA receptor modulator, promoted sleep in rats and rhesus monkeys that was marked by REM sleep suppression, but had inconsistent effects in mice and paradoxically promoted wakefulness in dogs. Active-phase treatment of rats with DORA-12 similarly promoted NREM and REM sleep to magnitudes nearly identical to those seen during normal resting-phase sleep following vehicle treatment, whereas eszopiclone suppressed REM even to levels below those seen during the active phase. The qEEG changes induced by DORA-12 in rats also resembled normal resting-phase patterns, whereas eszopiclone induced changes distinct from normal active- or inactive-phase spectra. Co-dosing experiments, as well as studies in transgenic rats lacking orexin neurons, indicated partial overlap in the mechanism of sleep promotion by orexin and GABA modulation with the exception of the REM suppression exclusive to GABAA receptor modulation. Following REM deprivation in mice, eszopiclone further suppressed REM sleep while DORA-22 facilitated recovery including increased REM sleep.ConclusionDORAs promote NREM and importantly REM sleep that is similar in proportion and magnitude to that seen during the normal resting phase across mammalian animal models. While limited overlap exists between therapeutic mechanisms, orexin signaling does not appear involved in the REM suppression exhibited by GABAA receptor modulators. The ability of DORAs to promote proportional NREM and REM sleep following sleep deprivation suggests that this mechanism may be effective in alleviating recovery from sleep disturbance.

Dataset Information

GABAA receptor occupancy by subtype selective GABAA?2,3 modulators: PET studies in humans.

Publications

GABA<sub>A</sub> receptor occupancy by subtype selective GABA<sub>Aα2,3</sub> modulators: PET studies in humans.

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