Effects of GABA Modulator AZD7325 on Cortical Excitability

Summary

GABA (gamma-aminobutyric acid) is the main inhibitory compound in the human brain. Drugs that enhance its effects by binding on GABA receptors (e.g., benzodiazepines) are used to treat various diseases such as epilepsy, insomnia, anxiety or movement disorders. However, the use of these medications is often compromised due to their side effects, like sedation, cognitive impairment, and addiction.

Many of these side effects have been linked to a particular type of GABA receptor (GABA A alpha 1). Therefore, effort is being made to develop drugs that do not act on this receptor, but maintain their beneficial properties by acting on other types of GABA receptors. AZD7325 is a drug that selectively acts on GABA A alpha 2 and A alpha 3 receptors, but not A alpha 1. It has been tested in more than 700 people and so far proved to be generally well tolerated. Positron emission tomography (PET) study in humans demonstrated that AZD7325 binds to GABA A receptors in the brain after a single dose. Early clinical studies have shown that it has less sedative and cognitive adverse events as compared with a benzodiazepine lorazepam.

In this study, we will investigate its effects on short interval intracortical inhibition (SICI). SICI is neurophysiological marker of inhibitory processes in the motor cortex. It is obtained non-invasively by using transcranial magnetic stimulation (TMS). In TMS, magnetic impulses applied over the scalp that in turn induce a current in a small area of the brain. If applied over the motor areas of the brain, impulses result in muscle twitch that is recorded with surface electrodes. SICI is enhanced by certain drugs like benzodiazepines that act on GABA A alpha 1,2,3, and 5 receptor subtypes, but not by zolpidem acting solely on alpha 1 subtype. Because GABA A alpha 5 receptor subtype is less common in the cortex, it has been concluded that the drug effects on SICI are related to GABA A alpha 2 and alpha 3 receptors.

If AZD7325 proves to enhance SICI in healthy volunteers, this would create the grounds for the use of this medication to treat certain neurological disorders in which SICI has been found to be impaired (e.g., dystonia).

Conditions

• Healthy

Interventions

DRUG

2 mg AZD7325

A single 2 mg oral dose of AZD7325

DRUG

10 mg AZD7325

A single 10 mg oral dose of AZD7325

DRUG

Placebo

A single oral dose

Sponsors & Collaborators

• University College, London

  lead OTHER

Principal Investigators

• Martin Koltzenburg, Prof · Institute of Neurology, University College London

Study Design

Allocation

RANDOMIZED

Purpose

BASIC_SCIENCE

Masking

DOUBLE

Model

CROSSOVER

Eligibility

Min Age

18 Years

Max Age

55 Years

Sex

MALE

Healthy Volunteers

Yes

Timeline & Regulatory

Start

2014-09-30

Primary Completion

2015-08-31

Completion

2015-08-31

Countries

• United Kingdom

Study Locations