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.5HTRL construct using a cAMP biosensor assay. Four structurally related natural products – nuciferine, D-glaucine, boldine and bulbocapnine – were demonstrated to block Sm.5HTRL evoked 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.5HTRL antagonists as hypomotility-evoking drugs across different parasite life cycle stages.

Kinetic profiling an abundantly expressed planarian serotonergic GPCR identifies bromocriptine as a perdurant antagonist

“…This behavior likely contributes to the protracted paralysis of intact planarian worms exposed to bromocriptine, and represents an intriguing and exploitable aspect of receptor phenomenology for anthelmintic drug design. Second, in the companion paper (Chan et al., 2016a), we demonstrate the utility of this technology for characterizing the interaction of a group of structurally related aporphine ligands with a schistosome serotonergic GPCR (Sm.5HTR L ). Collectively, both studies evidence the capacity to characterize flatworm GPCR properties with a reporter technology compatible with HTS campaigns.…”

Invertebrate serotonin receptors: a molecular perspective on classification and pharmacology

“…In addition, 5-HT 7 receptors have been described in flatworms ( phylum Platyhelminthes; see Glossary), and this receptor family appears to be the dominant clade in these organisms. Multiple sequences have been found in the planarian Dugesia japonica (Saitoh et al, 1997;Nishimura et al, 2009), the parasitic worm Schistosoma mansoni (Patocka et al, 2014;Chan et al, 2016a) and the cestodes Echinococcus granulosus and Mesocestoides corti (Camicia et al, 2018). Genome searches predict the presence of additional 5-HT receptors in Platyhelminthes (Chan et al, 2015;Patocka et al, 2014), but they have not yet been characterized.…”

Unique pharmacological properties of serotoninergic G-protein coupled receptors from cestodes

“…The seminal idea of Mansour [ 17 ] about the potential use of 5-HT receptors as pharmacological targets in parasites has received support from recent data in planarians [ 23 ] and Schistosoma mansoni [ 18 , 24 , 25 ]. Pharmacological profiling of heterologously expressed flatworm 5-HT receptors revealed different pharmacological profiles between parasitic and human serotonin receptors and inhibitory effects of various 5-HT antagonists on motility [ 25 ].…”