Pharmacodynamic and pharmacokinetic effects of MK-0343, a GABA(A) alpha2,3 subtype selective agonist, compared to lorazepam and placebo in healthy male volunteers
Journal of Psychopharmacology 2008; 22 (1); 24-32;
Commented by , 31 May 2008
To assess pharmacologic and pharmacokinetic properties of the potential new anxiolytic agent a GABA-A α 2,3 subtype selective agonist, MK-0343.
MK-0343 will show similar effects to lorazepam, and greater that placebo, in reducing saccadic eye movements peak velocity (possibly related to anxiolytic effect). In addition MK-0343 would show less effect upon memory, movements and sedation compared to lorazepam, and a similar effect to placebo.
12 healthy male volunteers were entered into a four way crossover, double-blind, placebo controlled study. On 4 different days they received either placebo, 2mg lorazepam, 0.25mg MK-0343, or 0.75mg M-0343. The sequence of medication allocation was randomised, balanced for first order carry over.
Outcome measures were assessed regularly on each test day: Saccadic eye movements (marker of both sedation and anxiolytic activity), Visual Analogue Scales (calmness, alertness and mood), body sway (postural stability), word and picture recall and recognition tests (memory). In addition regular blood plasma was taken for pharmacokinetic modelling of MK-0343 and safety data.
Both MK-0343 doses caused significantly greater reduction in saccadic peak velocity, visual analogue scale alertness to a similar degree. Although both lorazepam and MK-0343 increased body sway compared with placebo, Lorezepam caused significantly greater body sway than MK-0343. Lorazepam was also associated with significantly greater time delay to correct answers on recognition testing compared to placebo and MK-0343.
Dr Christmas', Dr Hood's and Prof Nutt's comments
The GABA-A receptor structure exhibits significant heterogeneity. It comprises of 5 subunits that are interchangeable from six families, with a total of 17 different subunits (α (1-6), β (1-3), γ (1-3), δ, ε, σ (1-3)). The benzodiazepines (such as lorazepam in this paper) are potent anxiolytics with a rapid onset of effect. They bind to GABA-A receptors containing both α and γ subunits (ref. 1), showing no specificity for the α 1,2,3, and 5 subunits. However, the limitations of benzodiazepines are well known: including sedation, tolerance, ataxia and amnesia.
It is known that GABA-A receptors containing different subtypes have different distributions in the brain giving different physiological effects when activated (ref. 2). Under this hypothesis it may be possible to find GABA-A subtype specific agonists (or "GASSAs") that have the desirable anxiolytic effects of benzodiazepines, without the unwanted side effects.
Preclinical data has shown much promise with this regard; the sedative and amnestic properties of the benzodiazepines may be conferred by GABA-A receptors containing α1 subunits (ref. 3), while their anxiolytic actions may be from α2 and α3 subunits (ref. 3, ref. 4).
Clinically, the α1 specific agonist zolpidem has been used as a hypnotic for some years. Our group have recently found that an α5 selective inverse agonist (a5IA) can block the amnestic effects of alcohol without impacting upon other features of intoxication (ie ataxia, enjoyment, sedation etc) (ref. 5).
The pharmacodynamic results for MK-0343 presented here are in keeping with this body of evidence (MK-0343 is also a partial agonist α1 and α5 subunits in addition to a full agonist at α2 and α3 subunits); it shows evidence of anxiolysis with less propensity to cause amnesia and ataxia than a classical benzodiazepine. These results suggest that sedation may still also be a problem (possibly from the α1 partial agonism) and further work is required to determine if this occurs at a clinically anxiolytic doses.
MK-0343 is one of a series of GASSAs that are now undergoing trials in human subjects. Some such as pagoclone (α3 agonist and α1, α2 and α5 partial agonist) have been in clinical trials (ref. 6). These trials have produced some unusual results. An example is Ocinaplon, which is an α1 agonist and α2, α3, α5 partial agonist.
It has shown anxiolysis without sedation in a trial of generalised anxiety disorder (ref. 7), in which the lack of sedation is at odds with the preclinical studies and clinical use of zolpidem. The potential for α1 selective agonists to act as anxiolytics has also recently been investigated by our group using carbon dioxide challenge testing (ref. 8).
The experience with ocinaplon highlights the current limitations of animal models of anxiety and the need to continue to develop valid and reliable clinical tests of potential anxiolytics. GASSAs are currently one of the most exciting areas emerging in the pharmacology of anxiolysis and we await further developments in this field.
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