Structure-activity Profiling of Alkaloid Natural Product Pharmacophores Against a Schistosoma Serotonin Receptor

Overview

Journal Int J Parasitol Drugs Drug Resist

Publisher Elsevier

Specialty Parasitology

Date 2018 Oct 10

PMID 30297303

Citations 7

Authors

Jonathan S Marchant

Wayne W Harding

John D Chan

Affiliations

Soon will be listed here.

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, 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. 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 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 responses, provides greater understanding of pharmacophores selective for this target to aid future drug development efforts.

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