The anthelminthic drug praziquantel is a selective agonist of the sensory transient receptor potential melastatin type 8 channel

Praziquantel activates a schistosome transient receptor potential channel

“…(R)-PZQ acts as a partial agonist of the human 5-hydroxytryptamine 2B receptor (5HT 2B R, [8]) and (S)-PZQ is a partial agonist of the human transient receptor potential melastatin-8 channel (hTRPM8, [9]). While regulation of these host targets occurs over a micromolar concentration range (EC 50 for ±PZQ at 5-HT 2B R ~8µM [8], EC 50 for ±PZQ at hTRPM8 ~20-25µM [9,10]), molecular divergence between human and flatworm ligand binding pockets [11,12] makes it reasonable to anticipate different affinities at homologous schistosome target(s). Full concentration-response curves were performed with (R)-PZQ ( Figure 2C), (S)-PZQ and ±PZQ ( Figure 2D).…”

Praziquantel Resistance in the Zoonotic Cestode Dipylidium caninum

“…The exact mechanism of praziquantel action is yet to be fully elucidated, and new targets are being studied to fully account for drug activity. 24 One well-studied and widely accepted target of praziquantel is the cestode voltage-gated calcium channels. 21 In our study, we cloned a partial sequence of the beta subunit of the voltage-gated calcium channel from the resistant cestodes, but analysis was constrained by the complete lack of availability of genome sequences of D. caninum.…”

Activation of host transient receptor potential (TRP) channels by praziquantel stereoisomers

“…mansoni worms from the splanchnic beds to the liver on administration [ 9 ] despite the appreciated lack of efficacy of (S)-PZQ against worms in vitro . Recent work has revealed activity of ±PZQ against the human transient receptor potential melastatin 8 channel (TRPM8, [ 15 ]), although the efficacy of the individual enantiomers at regulating TRPM8 are undefined. TRP channels belong to a superfamily of ion channels that respond to a broad diversity of stimuli and chemotypes underpinning many elements of our sensory physiology [ 16 , 17 ].…”

“…Schistosome TRPs are themselves promising targets for their druggability [ 18 , 19 ]. Collectively, both recent reports underscore considerable progress in defining activities and target(s) of ±PZQ action in the human host [ 13 , 15 ].…”

“…Here, we report a novel vasodilatory action of (S)-PZQ in contracted mesenteric vessels. Based on previously published data implicating TRPM8 channels in this vasodilatory effect in rat mesenteric arteries [ 20 ], further prioritized by the work of Babes et al [ 15 ] showing activation of TRPM8 by ±PZQ, activity of ±PZQ on endogenous TRPs that regulate myogenic tone was suspected. This study was designed to investigate the interaction of ( R )-PZQ and ( S )-PZQ with human TRPs, and test the possibility that such interactions regulate mesenteric vessel tone.…”