MICA: Valium without the sedation: Non-sedating anxiolytic 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 revolutionize the treatment of anxiety disorders in general and GAD in particular.

Generalised anxiety disorder (GAD) has a lifetime prevalence of 5% and is a debilitating disorder that produces a functional impairment that is comparable to major depressive disorder. It has an estimated UK societal cost of c.£10 billion/year, largely due to the significant limitations of current treatments. Hence, only around 25% of GAD patients are adequately treated due to a lack of efficacy and/or appreciable side effects and the paucity of effective treatments results in over half of patients remaining untreated. Therefore, since approaching 90% of patients receive inadequate or no treatment, there is a large unmet need for new drugs to treat GAD.
Benzodiazepines, typified by diazepam (Valium), have rapid and robust anxiolytic efficacy but their clinical utility is limited by side-effects, most notably sedation, and the search for a non-sedating anxiolytic has continued since Valium was introduced over 50 years ago but with little success, until recently. Benzodiazepines are positive allosteric modulators (PAMs) of four GABAA receptor (GABAAR) subtypes (i.e., GABAAR a1/a2/a3/a5 PAMs). Recent evidence suggests that by avoiding effects at the a1 (sedation) subtype, GABAAR a2/a3 PAMs should be non-sedating anxiolytics. Such compounds, AZD7325 and TPA023, were identified by AstraZeneca and Merck and in man both were non-sedating with preliminary anxiolytic-like efficacy. However, both companies stopped development of these drugs and their GABAAR a2/a3 PAM projects for a variety of reasons unrelated to the mechanism. Encouraged by the robust preclinical and preliminary clinical proof of concept, this proposal aims to build upon these data and identify novel non-sedating anxiolytic GABAAR a2/a3 PAMs. Such compounds will be suitable for early preclinical development with the ultimate aim being the identification of a first-in-class, non-sedating anxiolytic - "Valium without the sedation" - which could transform the treatment of GAD and other anxiety disorder

The most obvious beneficiaries of the GABAAR a2/a3 PAMs originating from this project are the roughly 1-1.5 million people in the UK that suffer from generalised anxiety disorder (GAD) each year. This is a debilitating disorder producing a functional impairment on a par with major depression and although there are a number of drugs approved for treating GAD, these drugs have significant limitations. Hence, the selective serotonin and serotonin/noradrenaline reuptake inhibitors (SSRIs and SNRIs) and benzodiazepines have appreciable side effects and, in the case of SSRIs and SNRIs modest efficacy. These limitations result in large number of GAD patients being inadequately treated or avoiding treatment due to the side effects. Consequently, a novel, non-sedating anxiolytic drug has the potential to revolutionise the treatment of GAD and become the first-line treatment option.
Additional beneficiaries could include subjects with pain disorders or autism. For example, GABAAR a2/a3 PAMs have been shown to demonstrate efficacy in animal models of these disorders. Moreover, as the scientific community use published tool compounds and those coming from this project to further explore GABAAR-related physiology and pathophysiology, then so additional indications may become apparent once the sedation observed with benzodiazepines is dialled-out.