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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.

Authors :
Marchant JS
Harding WW
Chan JD
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.)

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