In neuronal circuits of the mammalian central nervous system, inhibition of activity is driven by proteins named gamma aminobutyric acid type A receptors (GABAARs). For this reason, therapies that require neuroinhibition (for example, against the neuronal hyperactivity observed in pain or epilepsy) are often based on drugs that potentiate GABAARs. However, due to their widespread expression and strong inhibitory action, systemic pharmaceutical potentiation of GABAARs inevitably causes adverse effects regardless of the drug selectivity. Therefore, therapeutic guidelines must often limit or exclude clinically available GABAAR 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 ondemand, localized illumination. However, a suitable light-activated potentiator of GABAARs has been elusive so far for use in wildtype mammals.
To meet this need, a collaborative effort between the Institute for Bioengineering of Catalonia (IBEC) and the Forschungszentrum Jülich have developed azocarnil, a diffusible GABAergic agonist-potentiator based on the anxiolytic drug abecarnil that is inactive in the dark and activated by visible violet light. Azocarnil can be rapidly deactivated with green light and by thermal relaxation in the dark. This photoswitchable drug selectively inhibits neuronal currents in hippocampal neurons in vitro and in the dorsal horns of the spinal cord of mice, decreasing the mechanical sensitivity as a function of illumination without displaying systemic adverse effects. Azocarnil expands the in vivo photopharmacological toolkit with a novel chemical scaffold and achieves a milestone toward future phototherapeutic applications to safely treat muscle spasms, pain, anxiety, sleep disorders, and epilepsy.
