Recent Advances on GABAB Receptor Positive Allosteric Modulators as Potential Pharmacotherapies for Neuropsychiatric Disorders

The GABAB receptors have long been implicated in the pathophysiology of neuropsychiatric disorders such as schizophrenia, bipolar disorder, major depression, anxiety, epilepsy, chronic pain, autism, and substance use disorders, among others. In this direction, a number of GABAB receptor agonists were developed, one of which, baclofen, has been approved for clinical use for the treatment of muscle spasms related to multiple sclerosis and spinal cord injuries. Other GABAB receptor agonists were also developed and extensively examined at a preclinical level for their effects in a number of neuropsychiatric conditions. However, all GABAB receptor agonists exhibit moderate or severe side effects, including, but not restricted to, drowsiness, dizziness, weakness, and tolerance. In the last couple of decades, a number of GABAB receptor positive allosteric modulators (PAMs) were developed; these are molecules that bind onto a different (i.e., allosteric) site on the GABAB receptor to the one where GABA or GABAB receptor agonists bind, and promote the release of GABA, but lack the intrinsic properties of GABAB receptor agonists; thus, they show a better pharmacological profile, and they exhibit less side effects than the agonists in behavioral studies. This chapter aims to capture the history and recent advances on the role of GABAB PAMs as potential pharmacotherapies for neuropsychiatric disorders.