Pharmaceutics and Drug Design Commons^™

Structure-Activity Profiling Of Alkaloid Natural Product Pharmacophores Against A Schistosoma Serotonin Receptor, Jonathan S. Marchant, Wayne W. Harding, John D. Chan

Publications and Research

Serotonin (5-HT) is an important regulator of numerous aspects of flatworm biology, ranging from neuromuscularfunctionto sexualmaturationandegglaying. Intheparasiticblood flukeSchistosomamansoni,5-HTtargets 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 …