TY - JOUR T1 - Simple 2,4 diacylphloroglucinols as TRPC6 activators - identification of a novel pharmacophore. JF - Molecular Pharmacology JO - Mol Pharmacol DO - 10.1124/mol.109.057513 SP - mol.109.057513 AU - Kristina Leuner AU - Jeanine H Heiser AU - Swetlana Derksen AU - Mitko I. Mladenov AU - Christian J. Fehske AU - Rudolf Schubert AU - Maik Gollasch AU - Gisbert Schneider AU - Christian Harteneck AU - Shyam S. Chatterjee AU - W. E. Muller Y1 - 2009/12/14 UR - http://molpharm.aspetjournals.org/content/early/2009/12/14/mol.109.057513.abstract N2 - The naturally occurring acylated phloroglucinol derivative hyperforin was recently identified as the first specific TRPC6 activator. Hyperforin is the major antidepressant component of St. John's wort, which mediates its antidepressant-like properties via TRPC6 channel activation. However, its pharmacophore moiety for activating TRPC6 channels is unknown. We hypothesised that the phloroglucinol moiety could be the essential pharmacophore of hyperforin and that its activity profile could be due to structural similarities with DAG, an endogenous nonselective activator of TRPC3, TRPC6, TRPC7. Accordingly, a few 2-acyl and 2,4-diacylphloroglucinols were tested for their hyperforin-like activity profiles. We used a battery of experimental models to investigate all functional aspects of TRPC6 activation, including ion channel recordings, Ca2+ imaging, neurite outgrowth, and inhibition of synaptosomal uptake. Phloroglucinol itself was inactive in all our assays, which was also the case for 2-acylphloroglucinols. For TRPC6 activation, the presence of two symmetrically acyl-substitutions with appropriate alkyl chains in the phloroglucinol moiety seem to be an essential prerequisite. Potencies of these compounds in all assays were comparable to that of hyperforin for activating the TRPC6 channel. Finally, using structure-based modelling techniques a binding mode for hyperforin to TRPC6 is suggested. Based on this modelling approach, we propose that DAG is able to activate all three TRPC3, TRPC6, TRPC7 due to higher flexibility within the chemical structure of DAG compared to the rather rigid structures of hyperforin, and the 2,4-diacylphloroglucinol derivatives.The American Society for Pharmacology and Experimental Therapeutics ER -