Structure-Property Relationships in Novel Series of Photoswitchable Local Anesthetic Ethercaine Derivatives: Emphasis on Biological and Photophysical Properties.

The insufficient selectivity of existing local anesthetics can lead to serious adverse effects. Considering the widespread use of this class of drugs, the development of new local anesthetics that do not cause side effects is an important task. One approach to address this issue is the use of photopharmacology, which enables the creation of agents with light-controlled biological activity. Several examples of azobenzene-based photoswitchable blockers of voltage-gated sodium (Na) channels have been described so far. These compounds can be used as light-controlled local anesthetics, one of which is ethercaine, synthesized by our group earlier. However, systematic studies of the "structure-activity" relationship in the series of light-controlled local anesthetics based on azobenzene are absent in the literature. The aim of this study was to obtain new derivatives of ethercaine and investigate their photophysical and biological properties. A total of 14 new derivatives were synthesized, and their structure was confirmed by various physicochemical analysis methods. The Z-E isomerization half-lifes were determined for all the synthesized compounds. The cytotoxic effect on normal cells was studied in vitro using human dermal fibroblasts (DF2). The local anesthetic activity of all the synthesized compounds was evaluated in vivo on a model of surface anesthesia in both darkness and under UV light irradiation. Based on the results obtained, conclusions were drawn regarding the potential of the proposed substances, and optimal pathways for structural modification were identified.