EXPLORING SEROTONIN-GATED ION CHANNELS THROUGH REPURPOSING STRATEGIES

NOELIA RODRIGUEZ ARAUJO; GUILLERMINA HERNANDO ; CECILIA BOUZAT

Mar del Plata

Congreso; REUNIÓN CONJUNTA SAIC SAB AAFE AACYTAL 2023; 2023

SAIC SAB AAFE AACYTAL

A drug repurposing strategy that considers the chemical structureand molecular action on serotonergic Cys-loop receptors offers valuable guidance for the rational reuse of existing drugs, thereby reducing the time and costs associated with developing new medications.We focused on nematode and vertebrate 5-HT-gated ion channelsand tested several drugs in clinical use using electrophysiologicaltechniques. In nematodes, a unique serotonin-activated chloridechannel, MOD-1, is emerging as a new target for antiparasiticdrugs. In humans, 5-HT3A is involved in emesis and is an importantplayer in the enteric nervous system. We previously demonstratedthat tryptamine and its derivatives could be good candidates foranthelmintic therapy, acting on the serotonin MOD-1 receptor. Wefound that sumatriptan and eletriptan, from the triptan family, inhibit5-HT-induced currents of MOD-1 receptor in a concentration-dependent manner. By using the nematode Caenorhabditis elegans,we revealed the anthelmintic actions of sumatriptan and eletriptanat the behavioral level. Our locomotor activity assays showed thatboth drugs produced a decrease in worms’ activity, with eletriptanbeing more potent than sumatriptan. Mutants lacking MOD-1 werepartially resistant to both drugs. Also, we revealed novel aspectsof MOD-1 function from the molecular level to the organism level,which may contribute to provide new directions for anthelmintic drugdiscovery and drug repurposing. By electrophysiology techniqueswe revealed that the anthelmintic piperazine (PZE), which acts atnematode GABA and MOD-1 receptors, decreased human 5-HT3Amacroscopic currents elicited by 5-HT. The analysis showed thatPZE acts as a negative allosteric modulator; thus PZE or its derivatives may be explored as promising therapeutic tools that may replace classical orthosteric antagonists. Our drug repurposing strategy contributes to identify new targets and potential uses of drugson a rational basis.