Psychoactive Drugs as a Route to Development of Novel Anti‐parasitic Agents

Abstract

Over a third of the world's population is infected with parasitic worms. One of the most burdensome infections underpins the neglected tropical disease schistosomiasis (Bilharzia) caused by parasitic flatworms of the genus Schistosoma, which afflicts ~200 million people worldwide. Consequently, there is a need to discover and develop next generation anthelmintics, active against a broad spectrum of parasitic helminths.Flatworm musculature is regulated by bioaminergic signalling: addition of exogenous 5‐HT to isolated flatworm muscle fibres causes contraction. This effect is likely mediated by engagement of serotonergic G protein coupled receptors (GPCRs). For example, in free living planarians, knockdown of a serotonergic GPCR (S7.1) impairs worm motility. Here, we demonstrate that the psychoactive agent, lysergic acid diethylamide (LSD) acts as a agonist at the planarian S7.1 receptor (EC50 = 1.3±0.5nM, Emax 99±5% of 5‐HT response). LSD evoked contraction inhibited the motility of free living planarian worms (distance moved 16±2% versus control worms) and potently blocked bipolar regeneration evoked by praziquantel (IC50 = 0.5±0.2nM). These data raises the possibility that other psychoactive drugs, including psychotropics with known activity at human 5‐HT2 receptors, could serve as efficacious lead compounds to disrupt flatworm mobility.Therefore, we screened a variety of psychoactive agents on the motility of free living planarian flatworms, as well as the functionality of heterologously expressed S7.1 using a real time cAMP biosensor. Agents were discovered that modulated flatworm movement and regeneration, and efficacy of the screened molecules provided information about structural features necessary for activity at this abundant flatworm serotonergic GPCR. These data also identify features of ligands conveying activity at flatworm 5‐HT GPCRs.Support or Funding InformationSupported by NSF (MCB1615538, to JSM).