The Anthelmintic Activity of Praziquantel Analogs Correlates with Structure–Activity Relationships at TRPM(PZQ) Orthologs

[Image: see text] The anthelmintic drug praziquantel remains a key clinical therapy for treating various diseases caused by parasitic flatworms. The parasite target of praziquantel has remained undefined despite longstanding usage in the clinic, although a candidate ion channel target, named TRPM(PZQ), has recently been identified. Intriguingly, certain praziquantel derivatives show different activities against different parasites: for example, some praziquantel analogs are considerably more active against cestodes than against schistosomes. Here we interrogate whether the different activities of praziquantel analogs against different parasites are also reflected by unique structure–activity relationships at the TRPM(PZQ) channels found in these different organisms. To do this, several praziquantel analogs were synthesized and functionally profiled against schistosome and cestode TRPM(PZQ) channels. Data demonstrate that structure–activity relationships are closely mirrored between parasites and their TRPM(PZQ) orthologs, providing further support for TRPM(PZQ) as the therapeutically relevant target of praziquantel.