Structure-activity profiling of alkaloid natural product pharmacophores against a Schistosoma serotonin receptor

Abstract Serotonin (5-HT) is an important regulator of numerous aspects of flatworm biology, ranging from neuromuscular function to sexual maturation and egg laying. In the parasitic blood fluke Schistosoma mansoni , 5-HT targets several G-protein coupled receptors (GPCRs), one of which has been demonstrated to couple to cAMP and regulate parasite movement. This receptor, Sm.5HTR L , has been successfully co-expressed in mammalian cells alongside a luminescent cAMP-biosensor, enabling pharmacological profiling for candidate anti-schistosomal drugs. Here, we have utilized this assay to perform structure-activity investigations of 143 compounds containing previously identified alkaloid natural product pharmacophores (tryptamines, aporphines and protoberberines) shown to regulate Sm.5HTR L . These experiments mapped regions of the tryptamine pharmacophore amenable and intolerant to substitution, highlighting differences relative to orthologous mammalian 5-HT receptors. Potent Sm.5HTR L antagonists were identified, and the efficacy of these compounds were evaluated against live adult parasites cultured ex vivo . Such structure-activity profiling, characterizing the effect of various modifications to these core ring systems on Sm.5HTR L responses, provides greater understanding of pharmacophores selective for this target to aid future drug development efforts.