Gurrell, Rachel (2021) Translational pharmacology in action : the research and development of darigabat, an α2/3/5-subtype selective GABAA receptor positive allosteric modulator. (PhD thesis), Kingston University, .
Abstract
Benzodiazepines (BZDs), non-selective positive allosteric modulators (PAMs) of GABAA receptors, are highly efficacious across a range of therapeutic indications. However, even at low receptor occupancy (RO), BZDs are associated with significant side effects such as somnolence and are liable to abuse and to the development of tachyphylaxis, all of which limit their clinical utility, particularly in chronic indications such as epilepsy. As many of these undesirable properties are mediated by α1 subunit-containing GABAA receptors, there has been a concerted effort to develop α2/3/5 subtype selective PAMs for chronic treatment of a range of neurological and neuropsychiatric disorders. This thesis highlights the biomarker-enabled approach taken in the research and development program of darigabat, a compound identified as demonstrating the desired functional selectivity for GABAA receptors containing α2/3/5 subunits, with negligible activity at α1 subunits. The wide-ranging biomarker toolkit employed in both preclinical and clinical studies included measures of receptor occupancy, pharmacodynamic activity, and efficacy, and was designed to answer some key research questions. These included demonstrating the translation of the in vitro darigabat profile to the clinical profile; identifying attributes that differentiated GABAA receptor subtype-selective PAMs from BZDs (a critical requirement for the continued development of darigabat); understanding the relationship between darigabat dose, occupancy, and pharmacology; and has provided some understanding of the potential utility of darigabat in a range of CNS disorders. This work, which spans more than 10 years, has not only identified the therapeutic potential of darigabat, which is currently in Phase 2 clinical trials in focal epilepsy and Phase 1 clinical trials in panic, but has furthered our understanding of GABAA receptor pharmacology and the promise these compounds hold for the treatment of serious and disabling disorders.
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