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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:We report the modification of MIDD0301, an imidazodiazepine GABAA receptor (GABAAR) ligand, using two alkyl substituents. We developed PI310 with a 6-(4-phenylbutoxy)hexyl chain as used in the long-acting β2-agonist salmeterol and PI320 with a poly(ethylene glycol) chain as used to improve the brain:plasma ratio of naloxegol, a naloxone analogue. Both imidazodiazepines showed affinity toward the GABAAR binding site of clonazepam, with IC50 values of 576 and 242 nM, respectively. Molecular docking analysis, using the available α1β3γ2 GABAAR structural data, suggests binding of the diazepine core between the α1+/γ2- interface, whereas alkyl substituents are located outside the binding site and thus interact with the protein surface and solvent molecules. The physicochemical properties of these compounds are very different. The solubility of PI310 is low in water. PEGylation of PI320 significantly improves aqueous solubility and cell permeability. Neither compound is toxic in HEK293 cells following exposure at >300 μM for 18 h. Ex vivo studies using guinea pig tracheal rings showed that PI310 was unable to relax the constricted airway smooth muscle. In contrast, PI320 induced muscle relaxation at organ bath concentrations as low as 5 μM, with rapid onset (15 min) at 25 μM. PI320 also reduced airway hyper-responsiveness in vivo in a mouse model of steroid-resistant lung inflammation induced by intratracheal challenge with INFγ and lipopolysaccharide (LPS). At nebulized doses of 7.2 mg/kg, PI320 and albuterol were equally effective in reducing airway hyper-responsiveness. Ten minutes after nebulization, the lung concentration of PI320 was 50-fold that of PI310, indicating superior availability of PI320 when nebulized as an aqueous solution. Overall, PI320 is a promising inhaled drug candidate to quickly relax airway smooth muscle in bronchoconstrictive disorders, such as asthma. Future studies will evaluate the pharmacokinetic/pharmacodynamic properties of PI320 when administered orally.

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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