Mechanism of action: Gamma-aminobutyric acid receptor A alpha 2 & 3 (GABAAα2,3) positive modulator

Preclinical pharmacology

AZD7325 is a high affinity, selective modulator of the GABAA receptor system, with differential binding and modulatory properties dependent on the particular GABAA subtype.  Binding affinity is high at GABAAα1, α2 and α3 (Ki of 0.5, 0.3 and 1.3nM, respectively), but not GABAAα5 (230nM). Using whole cell electrophysiology after specific expression of a GABAA subunit in Xenopus oocytes, AZD7325 did not display intrinsic agonist activity at any subtype, but potentiated the response of diazepam at Aα2 and Aα3 (43 and 45%, respectively at 100nM), but not Aα1 or Aα5. In contrast, AZD7325 acted as a full antagonist of zolpidem at Aα1 consistent with a lack of sedative liabilities in vivo.  Selectivity was >100-fold in a panel of 160 other receptors, ion channels and enzymes, with the closest secondary pharmacology target being melatonin MT1 receptor antagonism (IC50 of 126nM). AZD7325 also potentiated native GABA responses in neurons prepared from the rat prefrontal cortex, occupied brain binding sites in non human primates as assessed by PET (approximately 50% receptor occupancy at plasma levels of ~1 x Ki), and demonstrated efficacy in a number of rat anxiety models.

Safety and tolerability

AZD7325 has been administered orally to healthy volunteers at single doses of up to 100mg and repeated doses up to 50mg QD for 7 days. Adverse events were CNS in nature, and included dizziness, feeling of relaxation, euphoric mood, somnolence, and headache. These were transient, mild, and related to peak plasma concentrations. In patients, AZD7325 has been administered up to 15mg BID for 28 days. The most frequent adverse events being dizziness, headache, and somnolence although one grand mal convulsion was also reported and considered to be treatment related.

Preclinical toxicity studies of up to 3 month duration have been performed. These have identified pharmacologically mediated changes in behavior and, additionally, changes to heart rate, increases in cholesterol, AST and ALT, and also changes in hematology parameters.  No compound related histopathogical changes were found.

Clinical pharmacology

Receptor occupancy was measured by PET imaging in healthy volunteers; maximal occupancy was achieved at doses of 10mg, 20 and 30mg.

Two Ph2a General Anxiety Disorder studies have been conducted. In the first, AZD7325 was dosed at either 2 or 5mg BID or 10mg QD for 28 days achieving compound plasma exposures of ~4 x Ki. In the second, it was dosed at either 5 or 15mg BID for 28 days and compared with lorazepam. While the primary objective of greater efficacy vs. placebo and/or lorazepam, as assessed by the Hamilton Anxiety scale, were not met at any of the doses tested, the placebo response rate was considered to be high and reduction in other anxiety endpoints at 10mg and depression MADRS score were noted.

Suitable for and exclusions

Suitable for study in indications, sub-populations, and/or endpoints that are manifestly distinct from those previously studied for this compound or mechanism of action.

Preclinical reprotoxicology data are available and have not identified any specific risks. Women of child-bearing potential using highly effective contraception can be included.

Subjects with past or present symptoms of alcohol or drug abuse/dependence and/or subjects suspected of abusing alcohol or illicit or prescription medications should probably be excluded.

Additional Information

Clinical trials for this compound

See all of the clinical trials currently associated with this compound:

Publications for this compound

Find out more about this compound by reading related publications:

The effects of the nonselective benzodiazepine lorazepam and the α2 /α3 subunit-selective GABAA receptor modulators AZD7325 and AZD6280 on plasma prolactin levels

The central nervous system effects of the partial GABA-Aα2,3 -selective receptor modulatorAZD7325 in comparison with lorazepam in healthy males

Population pharmacokinetic modelling to assess clinical drug-drug interaction between AZD7325and midazolam

A clinical study to assess CYP1A2 and CYP3A4 induction by AZD7325, a selective GABA(A) receptor modulator - an in vitro and in vivo comparison

Gene information from the NCBi

This compound works on the following genes: