AZD7325 is an Orally Active GABAAα2,3 Positive Allosteric Modulator

Benzodiazepines are useful in the research of anxiety disorders. Benzodiazepines also is useful for symptomatic relief of various anxiety states related to diverse psychiatric disorders, including mood, psychotic and personality disorders. Moreover, Benzodiazepines elicit their pharmacological effects through allosteric modulation of GABAA receptors. Benzodiazepines have non-selective binding affinities and present full in vitro efficacy at the GABA-A receptors that contain subunits α1, α2, α3 or α5. Furthermore, Benzodiazepines display uniform positive allosteric modulation activity at all these subtype receptors. In particular, AZD7325 is a α2/α3 selective positive allosteric modulator (PAM) of GABAA.

The GABAA receptor is a target of commonly used antiepileptic drugs (AEDs) including Benzodiazepines, Barbiturates, and Valproate (VPA). GABAA receptors are heteropentameric chloride channels, containing α-, β- and γ-subunits, with multiple subtypes. In this study, researchers demonstrate that AZD7325 preferentially potentiates hippocampal inhibitory responses at synapses proximal to the soma of CA1 neurons.

AZD7325 is an orally administered, potent, selective gamma-amino-butyric acid (GABAA) α2,3 receptor modulator intended for the treatment of anxiety. In vitro, AZD7325 demonstrates functional specificity for the GABA-Aα2 and GABA-Aα3 receptor subtypes. Besides, AZD7325 exerts neutral antagonism at the α1-subunit and partial efficacy at the α2,3-subunits over the α5-subunit. In addition, AZD7325 reduces the risk for the benzodiazepine-like side effects, such as sedation and cognitive effects.

AZD7325 is more effective in modulating inhibitory postsynaptic currents (IPSCs) in 129.Scn1a+/− mice than F1.Scn1a+/− mice. Subsequently, AZD7325 demonstrates stronger effects on IPSCs in the seizure of resistant mouse strain consistent with higher α2 subunit expression.

To summarise, AZD7325 is a potent, selective GABAAα2,3 receptor modulator intended for the treatment of anxiety.

Nomura T, et al. Potentiating α2 subunit containing perisomatic GABAA receptors protects against seizures in a mouse model of Dravet syndrome. J Physiol. 2019 Aug;597(16):4293-4307.