Drug repurposing strategy targeting serotonin-gated ion channels

RODRIGUEZ ARAUJO, N.; HERNANDO, G.S.; BOUZAT, C.

Mar del Plata

Congreso; REUNIÓN CONJUNTA SAIC SAI&FAIC SAFIS 2022; 2022

Sociedad Argentina de Investigación Clinica, Sociedad Argentina de Inmunología y Sociedad Argentina de Fisiología

Drug repurposing is an effective strategy for identifying new therapeutic use(s) for currently available drugs. We focused on serotonin (5-HT)-gated ion channels of nematodes and vertebrates and tested a series of clinically used drugs by electrophysiological techniques. We studied a nematode serotonin-activated chloride channel, MOD-1, as a novel target for antiparasitic drugs, and the vertebrate 5-HT3A receptor as a drug target for the treatment of nausea, emesis, and irritable bowel syndrome. Receptors were expressed in mammalian cells and their function was measured by whole-cell recordings. Drug screening assays revealed that piperazine (PZE), an anthelmintic drug acting at nematode GABA receptors, decreased macroscopic currents elicited by 5-HT of MOD-1 (IC50 113±29 μM). The analysis indicated that PZE acts as a negative allosteric modulator of MOD-1. Moreover, motility assays using the nematode model Caenorhabditis elegans showed that the negative modulation impacts on worm behavior, thus confirming the inhibition of MOD-1 as a novel anthelmintic mechanism. We tested PZE derivatives acting as H1-antihistamine drugs and found that hydroxyzine inhibited MOD-1 responses whereas cetirizine did not have any effect. We also showed that tryptamine, which has significantly higher agonist efficacy for MOD-1 (α=80%) than for 5-HT3A (α=27%), affected worm motility, indicating that it can be a novel anthelmintic lead compound. Moreover, we found that sumatriptan, a tryptamine-derivative currently used for migraine, also inhibited MOD-1 currents elicited by 5-HT. In 5-HT3A studies, we found that PZE also decreased macroscopic responses elicited by 5-HT (IC50 238±89 μM), thus revealing a novel allosteric inhibitor of this receptor. Our drug repurposing approach contributes to identify new targets and novel pharmacological uses of clinical drugs on a rational basis.