Abstract

It is around 20 years ago that Hanns Mohler, Uwe Rudolph and colleagues pioneered the elegant use of alpha subunit point mutation mice to dissect the role of different GABAAR subtypes in mediating the pharmacological of benzodiazepines. These data formed the basis for the selective targeting of particular GABAAR subtypes to produce, for example, α2/α3-GABAAR positive allosteric modulators (PAMs) as non-sedating anxiolytics and α5-GABAAR negative allosteric modulators (NAMs) as cognition enhancers. Based upon these hypotheses, a number of drug companies produced compounds that progressed into clinical studies but none have yet to reach the market. This overview discusses whether this lack of failure of these drugs to translate into new therapeutics is related to incorrect underlying hypotheses (which it is probably not) or is more of consequence of the random stuff that happens during the drug discovery process (which is much more likely).
Despite being perceived of as a bit passé relative to newer and sexier drug targets (not that I’m a tad bitter at being perceived as a not-at-all scientifically sexy GABAAR pharmacologist), there nevertheless remains great potential for subtype-selective GABAAR modulators to deliver real patient benefit.