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Pharmacological profiling an abundantly expressed schistosome serotonergic GPCR identifies nuciferine as a potent antagonist.
Pharmacological profiling an abundantly expressed schistosome serotonergic GPCR identifies nuciferine as a potent antagonist.
- Source :
-
International journal for parasitology. Drugs and drug resistance [Int J Parasitol Drugs Drug Resist] 2016 Dec; Vol. 6 (3), pp. 364-370. Date of Electronic Publication: 2016 Jun 23. - Publication Year :
- 2016
-
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 <subscript>L</subscript> ), 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 <subscript>L</subscript> construct using a cAMP biosensor assay. Four structurally related natural products - nuciferine, D-glaucine, boldine and bulbocapnine - were demonstrated to block Sm.5HTR <subscript>L</subscript> 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 <subscript>L</subscript> , and demonstrate the effectiveness of Sm.5HTR <subscript>L</subscript> antagonists as hypomotility-evoking drugs across different parasite life cycle stages.<br /> (Copyright © 2016 The Authors. Published by Elsevier Ltd.. All rights reserved.)
- Subjects :
- Animals
Drug Evaluation, Preclinical methods
Locomotion drug effects
Anthelmintics pharmacology
Aporphines pharmacology
Receptors, G-Protein-Coupled antagonists & inhibitors
Schistosoma mansoni drug effects
Schistosoma mansoni enzymology
Serotonergic Neurons drug effects
Serotonin Antagonists pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 2211-3207
- Volume :
- 6
- Issue :
- 3
- Database :
- MEDLINE
- Journal :
- International journal for parasitology. Drugs and drug resistance
- Publication Type :
- Academic Journal
- Accession number :
- 27397763
- Full Text :
- https://doi.org/10.1016/j.ijpddr.2016.06.001