2024 BIST Ignite Project: SWITCH

Project overview

Gamma aminobutyric acid type A receptors (GABA_ARs) play a key role in the mammalian central nervous system (CNS) as drivers of neuroinhibitory circuits, which are commonly targeted for therapeutic purposes with potentiator drugs. However, due to their widespread expression and strong inhibitory action, systemic pharmaceutical potentiation of GABA_ARs inevitably causes adverse effects regardless of the drug selectivity. Therefore, therapeutic guidelines must often limit or exclude clinically available GABA_AR potentiators despite their high efficacy, good biodistribution, and favorable molecular properties. One solution to this problem is to use drugs with light-dependent activity (photopharmacology) in combination with on-demand, localized illumination. However, a suitable visible light-activated potentiator of GABA_ARs has been elusive so far for use in wildtype mammals.

The SWITCH project proposes meeting this need by developing photoswitchable diffusible GABAergic potentiators. Leveraging the expertise in both synthesis and chemical biology of the research groups, SWITCH aims to design and synthesize several analogs, characterize their photochemical properties, and test them in vitro and in small animal models. These compounds may selectively inhibit neuronal currents in cultured neurons in vitro as a function of illumination, and open the way to treat muscle spasms, pain, anxiety, sleep disorders, and epilepsy without displaying systemic adverse effects.