AZD6280, a Novel Partial γ-Aminobutyric Acid A Receptor Modulator, Demonstrates a Pharmacodynamically Selective Effect Profile in Healthy Male Volunteers

Abstract

The SPV responses to AZD6280 suggest potential concentration-related anxiolytic effects, whereas the smaller SPV-normalized effects of AZD6280 on various non-SPV pharmacodynamic parameters suggest a more favorable side effect profile compared to lorazepam. Overall, the pharmacodynamic profile of AZD6280 matches the pharmacological specificity and selectivity of this compound at the α2,3 γ-aminobutyric acid A receptor subtypes.

Pharmacodynamic response profiles of anxiolytic and sedative drugs

“…Based on the putative link between GABA‐A α 2,3 receptors and anxiety , this supports the consideration of SPV as a biomarker of clinical anxiolysis associated with GABA α 2,3 activation , and the predictivity of SPV was supported by the selective SPV‐reduction caused by TPA023 , combined with early clinical findings of this partial GABA α 2,3 agonist . BZPs also affected body sway, VAS alertness , adaptive tracking and VAS calmness , suggesting impairment of postural balance, subjective alertness, eye–hand coordination, and subjective calmness, respectively . Given the clinical relevance of these PD parameters, scatter plots of each PD measurement against simultaneously obtained SPV values were depicted to demonstrate SPV‐normalized effect profiles with the study treatments.…”

GABAA receptor occupancy by subtype selective GABAAα2,3 modulators: PET studies in humans

“…It is tempting to speculate that the reduced intrinsic activity of AZD7325 was sufficient to diminish sedative side effects but was too low to achieve optimal anxiolytic activity. Importantly though, clear pharmacodynamic effects of both compounds were observed in the human volunteer studies using psychometric tests and EEG (Chen et al 2014, 2015). These effects were qualitatively and quantitatively distinct from those of lorazepam, and it is quite possible that the therapeutic effect of GABA A receptor a2/3 subunit selective compounds may be more appropriate for other neuropsychiatric indications.…”

“…There were just numerically higher sedation scores in VAS alertness scale compared to placebo at 1 h post-dose of AZD6280 and lower mean correct answers on DSST at 2 h after administration at dose ≥20 mg, i.e., at the exposure corresponding to receptor occupancy of >60% (AZ data on file). Moreover, no cognitive or hypnotic side effects were either observed in subjects examined in detail using neurophysiological test battery at the doses up to 80% RO for AZD7325 and up to 60% RO for AZD6280 (Chen et al 2014, 2015). In contrast, at anxiolytic doses of non-selective positive allosteric modulators acting at the BZ site (diazepam, clonazepam, alprazolam, midazolam, lorazepam), significant drowsiness has been associated with low receptor occupancy, ranging from 2 to 30% (Shinotoh et al 1989; Pauli et al 1991; Sybirska et al 1993; Malizia et al 1996; Lingford-Hudges et al 2005).…”

“…Both compounds exert their function selectively via GABA A receptor subunits as characterized by high in vitro affinity to the α1, α2, and α3 subunits and low affinity to the α5 subunit (Suppl. Table 1) and are partial BZ site modulators with efficacy selective for α2β3γ2 or α3β3γ2 subunits, i.e., AZD6280 produces 32–34% and AZD7325 produces 15% of maximal diazepam response, respectively (Chen et al 2014, 2015, Suppl. Table 1).…”

“…In preclinical models, these compounds have potent anxiolytic-like effects without sedation and induce a distinct pharmacoEEG signature (Alhambra et al 2011; Christian et al 2015). Examination of pharmacodynamic effects in phase I clinical trials has shown a novel pattern of effects on EEG (reduction in delta and theta bands) by AZD7325 and AZD6280, as well as effects on saccadic peak velocity, a suggested marker of anxiolysis (Chen et al 2014, 2015). …”