GABA_A receptors are ligand-gated chloride channels and the main mediators of inhibitory synaptic transmission in the human brain. There are 19 genes encoding for GABA_A receptor subunits that assemble as pentamers, with the most common stoichiometry of two α, two β, and one γ subunit. The α5 subunit-containing GABA_A receptors are of particular interest given their specific expression pattern¹ and physiological properties². Multiple lines of evidence suggest that excessive neural activity in selected brain regions with consequent imbalance between excitatory/inhibitory neurotransmission underlie a variety of neurological disorders such as epilepsy, Autism Spectrum Disorder (ASD), Schizophrenia and Alzheimer’s disease. The presentation will highlight our effort to identify highly potent, selective GABA_A α5 PAMs from a program that already led to a clinical NAM asset (Basmisanil). Key medicinal chemistry concepts involved in the optimization of the ligands and structural determinants underlining the NAM-to-PAM switch will be disclosed. Finally, proof of concept studies with selected PAMs in disease-relevant animal models will be presented.

[1] Cyrille Sur, Luigia Fresu, Owain Howell, Ruth M. McKernan, John R. Atack, Brain Res., 1999, 822, 265-270.
[2] Hanns Mohler, Neuropharmacology, 2011, 60, 1042-1049.