NS11821, a partial subtype-selective GABA_A agonist, elicits selective effects on the central nervous system in randomized controlled trial with healthy subjects

Abstract

NS11821 is a partial GABAA agonist with relatively dominant α2,3 and α5 subtype efficacy but negligible α1 agonism. This first-in-human study was performed in healthy male subjects using a single-dose, parallel, double blind, placebo-controlled, randomized, dose-escalation study design. In total six cohorts (N=48) were enrolled. The eight subjects of each cohort received NS11821 (10 mg, 30 mg, 75 mg, 150 mg, 300 mg or 600 mg) or placebo in a 6:2 ratio. At low dose levels, NS11821 had a relatively low exposure and a more-than-proportional increase of the area under the curve and maximum plasma concentrations, probably due to poor solubility. Saccadic peak velocity decreased in a dose-related manner while limited impairments were seen on body sway and the visual analogue scale for alertness. The most common adverse events were somnolence and dizziness, which were more prominent with the higher doses. Although no positive control was used in this study, the results were compared post hoc with a Centre for Human Drug Research dataset for lorazepam 2 mg. The maximum saccadic peak velocity effects seemed comparable to the typical effects of lorazepam, whereas the other central nervous system effects were smaller. These results support the pharmacological selectivity of NS11821 and show that pharmacodynamic effective doses of NS11821 were safe and well tolerated in healthy subjects.

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.…”

“…The literature is less clear about the subjective effects of anxiolytic drugs in healthy volunteers. In general, inconsistent changes of VAS calmness have been reported for single doses of lorazepam (2 mg) and some α 2,3 ‐subtype selective GABA‐A agonists , even at dosages that are clinically more anxiolytic than the relatively low doses of alprazolam 1 mg or pregabalin 200 mg employed in the current study. These inconsistencies suggest that VAS calmness is a less reliable biomarker in studies where anxiety is not specifically stimulated.…”

“…By contrast, as a full GABA‐A agonist, alprazolam induced robust effects on most CNS parameters. Such generalized CNS‐depressive PDs is similar to that of other BZPs and can be explained by the nonselective modulation of alprazolam on different GABA‐A receptor subtypes, which constitute the most widely distributed inhibitory receptors in the CNS. Pregabalin and its congener gabapentin are more selective and affect the α2δ subunit of the voltage‐dependent calcium channel.…”

“…Previous studies suggested good sensitivity of SPV to the effect of BZPs [10] and α 2,3 subtype-selective GABA-A receptor modulators [21][22][23][37][38][39]. There is a close association between the effect size of BZPs for SPV-reduction and their administered doses [10].…”

Further evaluation of the potential anxiolytic activity of imidazo[1,5- a ][1,4]diazepin agents selective for α2/3-containing GABA A receptors

“…NS11394 (Mirza et al, 2008) which displayed agonistic activity for the α2, α3 and α5 subtypes was shown to be anxiolytic; however, they were also shown to decrease memory, likely due to the activation of the α5 subtype (Mirza et al, 2008) In fact, NS11394 had greater efficacy at GABA A α5 receptors than GABA A receptors constituted by other alpha subunits (Mirza et al, 2008). In contrast, the ligands reported here (cpds 7 and 8) also had affinity and efficacy as agonists of GABA A α5 receptors though were generally less than that at the other alpha subtypes examined as also exemplified from GABA currents recorded from Xenopus oocytes (Lewter et al, 2017).. NS11821, another molecule that positively modulates α2, α3, and α5-comprised GABA A receptors, was less sedating and produced less body sway and subjectively-reported sedation than lorazepam in humans (Zuiker et al, 2016). Additionally, continued research has seen a number of promising candidates fail due to pharmacokinetic complications or other adverse effects.…”