Analysis of hyperforin (St. John's wort) action at TRPC6 channel leads to the development of a new class of antidepressant drugs.

St. John's wort is an herb, long used in folk medicine for the treatment of mild depression. Its antidepressant constituent, hyperforin, has properties such as chemical instability and induction of drug-drug interactions that preclude its use for individual pharmacotherapies. Here we identify the transient receptor potential canonical 6 channel (TRPC6) as a druggable target to control anxious and depressive behavior and as a requirement for hyperforin antidepressant action. We demonstrate that TRPC6 deficiency in mice not only results in anxious and depressive behavior, but also reduces excitability of hippocampal CA1 pyramidal neurons and dentate gyrus granule cells. Using electrophysiology and targeted mutagenesis, we show that hyperforin activates the channel via a specific binding motif at TRPC6. We performed an analysis of hyperforin action to develop a new antidepressant drug that uses the same TRPC6 target mechanism for its antidepressant action. We synthesized the hyperforin analog Hyp13, which shows similar binding to TRPC6 and recapitulates TRPC6-dependent anxiolytic and antidepressant effects in mice. Hyp13 does not activate pregnan-X-receptor (PXR) and thereby loses the potential to induce drug-drug interactions. This may provide a new approach to develop better treatments for depression, since depression remains one of the most treatment-resistant mental disorders, warranting the development of effective drugs based on naturally occurring compounds.

Activation of membrane-located Ca2+ channels by hop beta acids and their tricyclic transformation products.

Beta-bitter acids of hops (lupulones) revealed sedative and antidepressant-like effects in animal studies. Transformation of ß-acids during beer brewing leads to the formation of tricyclic transformation products, which have a close structural analogy to hyperforin. The latter compound is responsible for the antidepressant activity of St. John's wort by activation of TRPC6 cation channels in neuronal-like cells leading to Ca2+ influx. In this study, nortricyclolupones, dehydrotricyclolupones, and tricyclolupones were isolated from a wort-boiling model and their structures were elucidated by UHPLC-DAD, UHPLC-ESI--MS/MS and 1D/2D-NMR spectroscopy. Beta-bitter acids and their transformation products induced Ca2+ influx in PC12 cells to the same extent as hyperforin. Application of a Ca2+-free environment abolished the Ca2+ elevation, indicating that the increase is mediated by influx across the plasma membrane. Thus, activation of neuronal-like Ca2+-channels by lupulones and tricyclolupones represent a novel mechanism contributing to the antidepressant activity of hops.