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Structure-activity profiling of alkaloid natural product pharmacophores against a Schistosoma serotonin receptor.
Structure-activity profiling of alkaloid natural product pharmacophores against a Schistosoma serotonin receptor.
- Source :
-
International journal for parasitology. Drugs and drug resistance [Int J Parasitol Drugs Drug Resist] 2018 Dec; Vol. 8 (3), pp. 550-558. Date of Electronic Publication: 2018 Sep 28. - Publication Year :
- 2018
-
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 <subscript>L</subscript> , 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 <subscript>L</subscript> . 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 <subscript>L</subscript> 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 <subscript>L</subscript> responses, provides greater understanding of pharmacophores selective for this target to aid future drug development efforts.<br /> (Copyright © 2018. Published by Elsevier Ltd.)
- Subjects :
- Alkaloids isolation & purification
Alkaloids therapeutic use
Animals
Biological Products administration & dosage
Biological Products chemistry
Biological Products therapeutic use
Female
HEK293 Cells
Humans
Mice
Receptors, G-Protein-Coupled antagonists & inhibitors
Receptors, Serotonin chemistry
Receptors, Serotonin metabolism
Schistosomiasis drug therapy
Serotonin administration & dosage
Serotonin Antagonists administration & dosage
Serotonin Antagonists pharmacology
Serotonin Antagonists therapeutic use
Alkaloids chemistry
Alkaloids pharmacology
Biological Products pharmacology
Receptors, Serotonin drug effects
Schistosoma mansoni drug effects
Serotonin pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 2211-3207
- Volume :
- 8
- Issue :
- 3
- Database :
- MEDLINE
- Journal :
- International journal for parasitology. Drugs and drug resistance
- Publication Type :
- Academic Journal
- Accession number :
- 30297303
- Full Text :
- https://doi.org/10.1016/j.ijpddr.2018.09.001