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Structure-activity profiling of alkaloid natural product pharmacophores against a Schistosoma serotonin receptor. Int J Parasitol Drugs Drug Resist 2018 12;8(3):550-558

Date

10/10/2018

Pubmed ID

30297303

Pubmed Central ID

PMC6287472

DOI

10.1016/j.ijpddr.2018.09.001

Scopus ID

2-s2.0-85054495610   8 Citations

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.5HTRL, 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.5HTRL. These experiments mapped regions of the tryptamine pharmacophore amenable and intolerant to substitution, highlighting differences relative to orthologous mammalian 5-HT receptors. Potent Sm.5HTRL 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.5HTRL responses, provides greater understanding of pharmacophores selective for this target to aid future drug development efforts.

Author List

Marchant JS, Harding WW, Chan JD

Author

Jonathan S. Marchant PhD Chair, Professor in the Cell Biology, Neurobiology and Anatomy department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Alkaloids
Animals
Biological Products
Female
HEK293 Cells
Humans
Mice
Receptors, G-Protein-Coupled
Receptors, Serotonin
Schistosoma mansoni
Schistosomiasis
Serotonin
Serotonin Antagonists
jenkins-FCD Prod-482 91ad8a360b6da540234915ea01ff80e38bfdb40a