GABA-B receptor modulators with functional selectivity - a putative new class of antidepressant drugs

Background: The clinical challenges and shortcomings with the existing pharmacotherapy of anxiety and depression require new pharmacological strategies. Recent models of disease neurobiology and pathology, as well as preclinical studies, point to the GABA-B receptor as a putative target for new drug development.
Hypothesis: Functional selectivity is the ability of a ligand to activate one signaling pathway of a receptor in front of others. Increased understanding of GABAB-R signaling indicates that allosteric modulators with functional selectivity promoting beneficial, while blocking potential deleterious pathways are promising candidates for the pharmacotherapy of anxiety and depression.
Methods: We have identified modulators of the GABA-B receptor, and now we will use these compounds to identify modulators with the beneficial functional selectivity. We will use a combination of structure based ligand design, organic synthesis, and in vitro functional assays. The most promising modulators will be tested in animal models evaluating their effect on fear, anxiety depression, learning and memory. The brain systems affected by the modulators will be identified with Positron Emission Tomography (PET) and Single Photon Emission Computed Tomography (SPECT).
Deliveries: The main deliveries from the project may be patentable innovative compounds that modulate GABA-B activity and have promising effects in animal models.