The allosteric modulation of the GABAB receptor: a medicinal chemistry perspective

Since its cloning, the GABAB receptor has progressively become a target for potential drugs to be used in the treatment of a wide range of pathological conditions such as spasticity, pain, drug addiction, epilepsy, anxiety, mood disorders. Baclofen, the only GABAB receptor agonist currently approved for the treatment of muscle rigidity and spasm associated with multiple sclerosis or spinal cord injury, suffers from a number of side effects which hamper its clinical use. As a result, there has been a strong impetus for the development of positive allosteric modulators that modulate the physiological mechanisms of GABAergic regulation and are expected to have a much lower side effect potential than orthosteric ligands. Herein, the major structural classes of GABAB allosteric modulators are described with an emphasis on structure–activity relationships (SAR) and synthesis of the main representatives of each class. Medicinal chemistry strategies to overcome issues related to allosteric modulators development are also discussed. © Springer International Publishing Switzerland 2016.