Recent Advances on the Chemistry of GABAB Receptor Allosteric Modulators

Allosteric modulation of therapeutic protein targets has been proposed as a possible strategy to overcome the limitations of orthosteric ligands. However, it has been shown that many of these protein systems, including the GABAB receptor, are quite difficult to target. The development of new allosteric modulators therefore represents a major challenge. To date, no therapeutic agent that can allosterically modulate the GABAB receptor has been used clinically. Nevertheless, academic and industrial research received a remarkable boost after the discovery of the first GABAB receptor positive allosteric modulators (PAMs) in 2001–2012, leading to the identification of new compounds with promising pharmacodynamic and pharmacokinetic properties. This enabled the preclinical and clinical development of the three candidates, ASP8062, ODM-106, and ADX71441, as potential treatments for substance use disorder or essential tremor. Although the clinical trials of ODM-106 and ADX71441 have been discontinued, many hopes are pinned on ASP8062, which could become the first GABAB receptor PAM of therapeutic interest. The period 2013–2018 has thus been a harbinger of very relevant innovations, including the discovery of negative allosteric modulators of the GABAB receptor, expanding the arsenal of pharmacological tools to study the involvement of this receptor in various pathological processes.