Structure-activity profiling of alkaloid natural product pharmacophores against a Schistosoma serotonin receptor

• Published in: International journal for parasitology -- drugs and drug resistance 2018-12, Vol.8 (3), p.550-558
• Main Authors: Marchant, Jonathan S., Harding, Wayne W., Chan, John D.
• Format: Article
• Language: English
• Subjects: Alkaloids - chemistry; Alkaloids - isolation & purification; Alkaloids - pharmacology; Alkaloids - therapeutic use; Animals; Aporphine; Benzylisoquinoline; Biological Products - administration & dosage; Biological Products - chemistry; Biological Products - pharmacology; Biological Products - therapeutic use; Female; from the scientific meeting: "Anthelmintics: From Discovery to Resistance III", pp. 494 - 628; G protein coupled receptor; HEK293 Cells; Humans; Mice; Protoberberine; Receptors, G-Protein-Coupled - antagonists & inhibitors; Receptors, Serotonin - chemistry; Receptors, Serotonin - drug effects; Receptors, Serotonin - metabolism; Schistosoma mansoni - drug effects; Schistosomiasis; Schistosomiasis - drug therapy; Serotonin - administration & dosage; Serotonin - pharmacology; Serotonin Antagonists - administration & dosage; Serotonin Antagonists - pharmacology; Serotonin Antagonists - therapeutic use; Tryptamine
• ISSN: 2211-3207; 2211-3207
• DOI: 10.1016/j.ijpddr.2018.09.001

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. [Display omitted] •Various alkaloids were screened against a schistosome serotonin receptor, Sm.5HTRL.•Compounds with a tryptamine core displayed agonist activity at Sm.5HTRL.•Aporphine and protoberberine compounds displayed antagonist activity at Sm.5HTRL.•Compound activity at Sm.5HTRL is broadly mirrored by motility effects on adult worms.