Donor-acceptor Stenhouse adduct-based photooswitch for GABA receptors

Photopharmacology is a rapidly evolving field of the life science, at the crossroads of modern pharmacology, photochemistry, biology, and personalized medicine. Photopharmacology is based on the ability of photochromic organic molecules to undergo a conformational change upon light exposure, consequently causing modifications in their chemical and physical properties. Photopharmacologycal approach was successfully employed for the light-driven control of various biological processes, especially in the nervous system. Recently we have developed a first photoswitchable channel blocker of GABA receptors, first photoswitchable fulgimide-based potentiator of GABAARs and first photoswitchable modulator of glycine receptors. Here, we demonstrate a new model compound – DASA-barbital, based on a scaffold of red-switching second-generation DASAs. Following the synthesis procedure, we have shown that DASA scaffold is amenable to rationally design red-switching barbiturate ligands. The UV-vis absorption spectrum of DASA- barbital in DMSO has shown a narrow absorption band around 615 nm that is consistent with the bright blue colour of the solution and makes it a molecule with unique photoswitching properties. DASA-barbital can be reversibly photoswitched in water using a pharmaceutical excipient. Biological activity of DASA-barbital was studied at cultured hippocampal neurons using current clamp and voltage clamp modes of patch-clamp technique. We have demonstrated that DASA- barbital can regulate the amplitude of spontaneous inhibitory postsynaptic currents and frequency of neuronal firing. Our results show that DASA-barbital is active in neurons via GABAARs, which raises exciting prospects for photopharmacology and neurobiology. Receptor binding is retained in the cyclic form despite its bulky structure and the absence of branching, which contrasts with most barbiturates. DASA-based neuroactive molecules are widely appealing because they can be photoswitched with red and near infra-red light.