Natural product inspired optimization of a selective TRPV6 calcium channel inhibitor

Rodrigues Cunha, Micael; Bhardwaj, Rajesh; Carrel, Aline Lucie; Lindinger, Sonja; Romanin, Christoph; Parise-Filho, Roberto; Hediger, Matthias A.; Reymond, Jean-Louis (2020). Natural product inspired optimization of a selective TRPV6 calcium channel inhibitor. RSC Medicinal Chemistry, 11(9), pp. 1032-1040. Royal Society of Chemistry 10.1039/D0MD00145G

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Transient receptor potential vanilloid 6 (TRPV6) is a calcium channel implicated in multifactorial diseases and overexpressed in numerous cancers. We recently reported the phenyl-cyclohexyl-piperazine cis-22a as the first submicromolar TRPV6 inhibitor. This inhibitor showed a seven-fold selectivity against the closely related calcium channel TRPV5 and no activity on store-operated calcium channels (SOC), but very significant off-target effects and low microsomal stability. Here, we surveyed analogues incorporating structural features of the natural product capsaicin and identified 3OG, a new oxygenated analog with similar potency against TRPV6 (IC50 = 0.082 ± 0.004 μM) and ion channel selectivity, but with high microsomal stability and very low off-target effects. This natural product-inspired inhibitor does not exhibit any non-specific toxicity effects on various cell lines and is proposed as a new tool compound to test pharmacological inhibition of TRPV6 mediated calcium flux in disease models.

Item Type:

Journal Article (Original Article)


04 Faculty of Medicine > Department of Dermatology, Urology, Rheumatology, Nephrology, Osteoporosis (DURN) > Clinic of Nephrology and Hypertension
04 Faculty of Medicine > Pre-clinic Human Medicine > Institute of Biochemistry and Molecular Medicine
08 Faculty of Science > Department of Chemistry, Biochemistry and Pharmaceutical Sciences (DCBP)
04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > Unit Childrens Hospital > Forschungsgruppe Nephrologie / Hypertonie

UniBE Contributor:

Rodrigues Cunha, Micael, Bhardwaj, Rajesh, Carrel, Aline Lucie, Hediger, Matthias, Reymond, Jean-Louis


600 Technology > 610 Medicine & health
500 Science > 570 Life sciences; biology
500 Science > 540 Chemistry




Royal Society of Chemistry




Sandra Tanja Zbinden Di Biase

Date Deposited:

10 Dec 2020 16:10

Last Modified:

05 Dec 2022 15:42

Publisher DOI:





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