N-(p-amylcinnamoyl)anthranilic acid (ACA): a phospholipase A(2) inhibitor and TRP channel blocker.
Phospholipase A(2) enzymes display a superfamily of structurally different enzymes classified in at least nine subfamilies by biochemical and structural properties. N-(p-amylcinnamoyl)anthranilic acid commonly referred to as ACA is often used as a broad-spectrum inhibitor for the characterization of phospholipase A(2)-mediated pathways. Compounds like ACA and ACA-like structures have been described to block the receptor-induced release of arachidonic acid and subsequent signaling cascades in the pancreas and the cardiovascular system. We showed that ACA directly blocks several transient receptor potential (TRP) channels (TRPC6, TRPM2, TRP and TRPM8). With respect to the published data of ACA in the phospholipase A(2) field, the finding that ACA blocks diacylglycerol-activated TRP channels is of specific interest as it offers the opportunity to interfere with receptor-induced calcium-dependent signaling processes in platelets and vascular smooth muscle cells. Overall, N-phenylcinnamides, as a new pharmaceutical lead structure, form the first class of synthetic TRP channel blockers and represent a promising start for the development of small organic TRP channel-specific blockers.
Harteneck
Christian
C
Institut für Pharmakologie, Charité - Universitätsmedizin Berlin, Berlin, Germany. Christian.Harteneck@charite.de
Frenzel
Henning
H
Kraft
Robert
R
D000818:Animals; D016718:Arachidonic Acid / Q000378:metabolism; D020013:Calcium Signaling / Q000187:drug effects; D002934:Cinnamates / Q000737:chemistry / Q000494:pharmacology*; D004075:Diglycerides / Q000378:metabolism; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D005439:Flufenamic Acid / Q000494:pharmacology; D006801:Humans; D015640:Ion Channel Gating / Q000187:drug effects; D015394:Molecular Structure; D010741:Phospholipases A / Q000037:antagonists & inhibitors* / Q000378:metabolism; D050052:TRPC Cation Channels / Q000037:antagonists & inhibitors* / Q000378:metabolism; D050053:TRPM Cation Channels / Q000037:antagonists & inhibitors; D062367:ortho-Aminobenzoates / Q000737:chemistry / Q000494:pharmacology*
D002934:Cinnamates; D004075:Diglycerides; D004791:Enzyme Inhibitors; D050052:TRPC Cation Channels; D050053:TRPM Cation Channels; C121934:TRPM2 protein, human; D062367:ortho-Aminobenzoates; C085901:4-amylcinnamoylanthranilic acid; D016718:Arachidonic Acid; D005439:Flufenamic Acid; D010741:Phospholipases A