GABAB Receptor Chemistry and Pharmacology: Agonists, Antagonists, and Allosteric Modulators

The GABAB receptors are metabotropic G protein-coupled receptors (GPCRs) that mediate the actions of the primary inhibitory neurotransmitter, γ-aminobutyric acid (GABA). In the CNS, GABA plays an important role in behavior, learning and memory, cognition, and stress. GABA is also located throughout the gastrointestinal (GI) tract and is involved in the autonomic control of the intestine and esophageal reflex. Consequently, dysregulated GABAB receptor signaling is associated with neurological, mental health, and gastrointestinal disorders; hence, these receptors have been identified as key therapeutic targets and are the focus of multiple drug discovery efforts for indications such as muscle spasticity disorders, schizophrenia, pain, addiction, and gastroesophageal reflex disease (GERD). Numerous agonists, antagonists, and allosteric modulators of the GABAB receptor have been described; however, Lioresal® (Baclofen; β-(4-chlorophenyl)-γ-aminobutyric acid) is the only FDA-approved drug that selectively targets GABAB receptors in clinical use; undesirable side effects, such as sedation, muscle weakness, fatigue, cognitive deficits, seizures, tolerance and potential for abuse, limit their therapeutic use. Here, we review GABAB receptor chemistry and pharmacology, presenting orthosteric agonists, antagonists, and positive and negative allosteric modulators, and highlight the therapeutic potential of targeting GABAB receptor modulation for the treatment of various CNS and peripheral disorders.