AZD-6280

Sedation, dependence, and abuse liability limit the use of non-selective γ-aminobutyric acid (GABA_A) receptor positive modulators for the treatment of anxiety. AZD7325 and AZD6280 are novel, subtype-selective GABA_Aα2,3 receptor positive modulators with limited sedative effects.

The current study aimed to confirm target engagement at GABA_A receptors by AZD7325 and AZD6280 in humans and to determine the relationship between exposure, GABA_A receptor occupancy, and tolerability.

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 (BP_ND) were obtained. The relationship between plasma concentration of AZD7325 or AZD6280 and GABA_A 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.

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.

High GABA_A receptor occupancy by AZD7325 and AZD6280 could be reached without clear sedative effects.

Compounds with selectivity for GABAA receptor subtypes may differ significantly from nonselective benzodiazepines in their dopaminergic effects in vivo. To explore the exact role of the GABAA receptor subtypes in the regulation of prolactin secretion and the differential effects of selective and nonselective GABA receptor modulators, the effects of the nonselective benzodiazepine lorazepam, as well as two novel α2/α3 subunit‐selective GABAA receptor modulators AZD7325 and AZD6280, on prolactin levels were measured in healthy male volunteers. Following administration of lorazepam at 2 mg doses and AZD6280 at 10 mg and 40 mg doses, prolactin levels increased significantly compared with placebo (difference 42.0%, 19.8%, and 32.8%, respectively), suggesting that the α2 and/or α3 receptor subtypes are involved in GABAergic modulation of prolactin secretion, although possible roles of the α1 and α5 receptor subtypes are not excluded. The increases in prolactin levels after administration of AZD7325 at 2 mg and 10 mg doses (difference 7.6% and 10.5%, respectively) did not reach statistical significance, suggesting that doses of AZD7325 or intrinsic efficacy at the α2 and α3 receptor subtypes may have been too low.