title: Pharmacological profiling an abundantly expressed schistosome serotonergic GPCR identifies nuciferine as a potent antagonist.
abstract: 5-hydroxytryptamine (5-HT) is a key regulator of muscle contraction in parasitic flatworms. In Schistosoma mansoni, the myoexcitatory action of 5-HT is effected through activation of a serotonergic GPCR (Sm.5HTRL), prioritizing pharmacological characterization of this target for anthelmintic drug discovery. Here, we have examined the effects of several aporphine alkaloids on the signaling activity of a heterologously expressed Sm.5HTRLconstruct using a cAMP biosensor assay. Four structurally related natural products - nuciferine, D-glaucine, boldine and bulbocapnine - were demonstrated to block Sm.5HTRLevoked cAMP generation with the potency of GPCR blockade correlating well with the ability of each drug to inhibit contractility of schistosomule larvae. Nuciferine was also effective at inhibiting both basal and 5-HT evoked motility of adult schistosomes. These data advance our understanding of structure-affinity relationships at Sm.5HTRL, and demonstrate the effectiveness of Sm.5HTRLantagonists as hypomotility-evoking drugs across different parasite life cycle stages.
authors.affiliation: Department of Pharmacology, University of Minnesota, Minneapolis, MN, 55455, USA.
authors.forename: John D
authors.initials: JD
authors.lastname: Chan
authors.affiliation: Department of Biomedical Sciences, Iowa State University, Ames, IA, 50011, USA.
authors.forename: Sreemoyee
authors.initials: S
authors.lastname: Acharya
authors.affiliation: Department of Biomedical Sciences, Iowa State University, Ames, IA, 50011, USA.
authors.forename: Timothy A
authors.initials: TA
authors.lastname: Day
authors.affiliation: Department of Pharmacology, University of Minnesota, Minneapolis, MN, 55455, USA; Stem Cell Institute, University of Minnesota, Minneapolis, MN, 55455, USA. Electronic address: march029@umn.edu.
authors.forename: Jonathan S
authors.initials: JS
authors.lastname: Marchant
mesh_terms: D000818:Animals; D000871:Anthelmintics / Q000494:pharmacology*; D001060:Aporphines / Q000494:pharmacology*; D004353:Drug Evaluation, Preclinical / Q000379:methods; D008124:Locomotion / Q000187:drug effects; D043562:Receptors, G-Protein-Coupled / Q000037:antagonists & inhibitors*; D012550:Schistosoma mansoni / Q000187:drug effects* / Q000201:enzymology*; D059326:Serotonergic Neurons / Q000187:drug effects*; D012702:Serotonin Antagonists / Q000494:pharmacology*
chemical_list: D000871:Anthelmintics; D001060:Aporphines; D043562:Receptors, G-Protein-Coupled; D012702:Serotonin Antagonists; C011686:boldine; C005004:glaucine; C083807:bulbocapnine; C008692:nuciferine
keywords: 5-HT; Methoxyisoquinoline; Natural products; Schistosomiasis