Valium without the sedation: Anxioselective GABAA receptor modulators for the treatment of anxiety disorders

This proposal aims to develop non-sedating anxiolytic drugs ("Valium without the sedation") that will represent the first major advance in the treatment of anxiety disorders for over 50 years. Anxiety disorders are the most common cause of patients visiting their GP and of these, generalized anxiety disorder (GAD) is the most prevalent. It affects around 5% of the population at some time in their life and is characterized by persistent, pervasive and excessive worrying. Consequently, it is a debilitating disorder that has an impact on society that is equivalent to depression and costs the UK in the region of £10 billion a year. Current treatments for GAD are unsatisfactory for various reasons and there have been no major innovations since benzodiazepines were introduced in the early 1960s. Benzodiazepines are a class of so-called minor tranquilizer drugs the most famous of which is diazepam (Valium, aka "Mother's Little Helper"). Benzodiazepines are effective at reducing anxiety (i.e., they are anxiolytics) but sedation is a major side-effect. Until recently, all attempts to identify next-generation drugs that "dial-out" these side-effects, particularly the sedation, have been unsuccessful. However, following recent advances in our knowledge of how benzodiazepines work, we are now in a position to understand what is required to develop a non-sedating anxiolytic and, more importantly, how we can identify such drugs. It is these breakthroughs in our knowledge that this proposal aims to exploit. Benzodiazepines act by altering the effects of a chemical in the brain (neurotransmitter) called gamma-aminobutyric acid (GABA). This neurotransmitter bind to four similar proteins in the brain called alpha1, alpha2, alpha3 and alpha5 GABAA receptors (GABAAR). Recent data suggests that the alpha1 subtype is responsible for sedation and consequently, it is hypothesised that by specifically affecting the alpha2 and alpha3 (the "anxiolytic") GABAAR subtypes while avoiding the alpha1 (the "sedation") subtype, it should be possible to identify an anxiolytic compound which is non-sedating. This hypothesis turns out to be correct with many experiments in animals showing that a GABAAR alpha2/alpha3 drug is indeed a non-sedating anxiolytic and early studies in man also support this hypothesis. Previous GABAAR alpha2/alpha3 drugs that were tested in man are no longer being developed due to a number of reasons unrelated to their mechanism of action and we therefore wish to continue with this area of research and develop novel GABAAR alpha2/alpha3 drugs that have the potential to revolutionise the treatment of anxiety disorders in general and GAD in particular.