2. Academic Validation
  3. Pharmacological profiling an abundantly expressed schistosome serotonergic GPCR identifies nuciferine as a potent antagonist

Pharmacological profiling an abundantly expressed schistosome serotonergic GPCR identifies nuciferine as a potent antagonist

  • Int J Parasitol Drugs Drug Resist. 2016 Dec;6(3):364-370. doi: 10.1016/j.ijpddr.2016.06.001.
John D Chan 1,  Sreemoyee Acharya 2,  Timothy A Day 2,  Jonathan S Marchant 3
Affiliations

Affiliations

  • 1 Department of Pharmacology, University of Minnesota, Minneapolis, MN, 55455, USA.
  • 2 Department of Biomedical Sciences, Iowa State University, Ames, IA, 50011, USA.
  • 3 Department of Pharmacology, University of Minnesota, Minneapolis, MN, 55455, USA; Stem Cell Institute, University of Minnesota, Minneapolis, MN, 55455, USA. Electronic address: [email protected].
PMID: 27397763 DOI: 10.1016/j.ijpddr.2016.06.001
Abstract

5-hydroxytryptamine (5-HT) is a key regulator of muscle contraction in parasitic flatworms. In Schistosoma mansoni, the myoexcitatory action of 5-HT is effected through activation of a serotonergic GPCR (Sm.5HTRL), prioritizing pharmacological characterization of this target for anthelmintic drug discovery. Here, we have examined the effects of several aporphine Alkaloids on the signaling activity of a heterologously expressed Sm.5HTRL construct using a cAMP biosensor assay. Four structurally related Natural Products - nuciferine, D-glaucine, boldine and bulbocapnine - were demonstrated to block Sm.5HTRL evoked cAMP generation with the potency of GPCR blockade correlating well with the ability of each drug to inhibit contractility of schistosomule larvae. Nuciferine was also effective at inhibiting both basal and 5-HT evoked motility of adult schistosomes. These data advance our understanding of structure-affinity relationships at Sm.5HTRL, and demonstrate the effectiveness of Sm.5HTRL antagonists as hypomotility-evoking drugs across different Parasite life cycle stages.

Keywords

5-HT; Methoxyisoquinoline; Natural products; Schistosomiasis.

Figures
Products