Pharmacological profiling an abundantly expressed schistosome serotonergic GPCR identifies nuciferine as a potent antagonist

John D. Chan; Sreemoyee Acharya; Timothy A. Day; Jonathan S. Marchant

doi:10.1016/j.ijpddr.2016.06.001

Pharmacological profiling an abundantly expressed schistosome serotonergic GPCR identifies nuciferine as a potent antagonist

John D. Chan, Sreemoyee Acharya, Timothy A. Day, Jonathan S. Marchant

Pharmacology

Research output: Contribution to journal › Article › peer-review

21 Scopus citations

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

Original language	English (US)
Pages (from-to)	364-370
Number of pages	7
Journal	International Journal for Parasitology: Drugs and Drug Resistance
Volume	6
Issue number	3
DOIs	https://doi.org/10.1016/j.ijpddr.2016.06.001
State	Published - Dec 1 2016

Bibliographical note

Funding Information:
This work was supported by NIH (AI125821). We are grateful for reagents provided by BEI Resources that enabled parasite assays.

Publisher Copyright:
© 2016 The Authors

Keywords

5-HT
Methoxyisoquinoline
Natural products
Schistosomiasis

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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.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.",

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Pharmacological profiling an abundantly expressed schistosome serotonergic GPCR identifies nuciferine as a potent antagonist

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Keywords

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