N‐(p‐Amylcinnamoyl)anthranilic Acid (ACA): A Phospholipase A₂ Inhibitor and TRP Channel Blocker

Abstract

Phospholipase A 2 enzymes display a superfamily of structurally different enzymes classified in at least nine subfamilies by biochemical and structural properties. N-(pamylcinnamoyl)anthranilic acid commonly referred to as ACA is often used as a broadspectrum 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 receptorinduced 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.

A Plant Ca2+ Pump, ACA2, Relieves Salt Hypersensitivity in Yeast

“…3, A-C). Ca 2ϩ release from the vacuole in response to hyperosmotic stress has been earlier shown to involve YVC1, a TRP channel (34) that could be a target of ACA (47). Indeed, the [Ca 2ϩ ] cyt transient we see in response to NaCl is attenuated in ACA-pretreated cells (supplemental Fig.…”

“…Identifying Candidate Signaling Intermediates That Regulate Salt Tolerance of K616-ACA2-ACA is reported to both inhibit phospholipase A2 and block TRP channels (47). ACA was preincubated with log phase cells of K601 and K616-ACA2 at sublethal doses (30 and 40 M), followed by an 18-h exposure to a range of NaCl (0 -1000 mM).…”

Sex Differences in Neuroprotection Provided by Inhibition of TRPM2 Channels following Experimental Stroke

“…For example, 2-aminoethoxy diphenyl borate was initially characterized as an antagonist of the inositol 1,4,5-triphosphate (InsP3) receptor (Maruyama et al, 1997) and more recently has been reported to inhibit several members of the TRPC and TRPM families, including TRPC1,3,5,6 and TRPM2,3,7,8 (for review see Ramsey et al, 2006). N-(p-amylcinnamoyl)anthranilic acid is a well-characterized phospholipase A 2 antagonist (Konrad et al, 1992;Harteneck et al, 2007), with minimal TRP channel targets, inhibiting only TRPC6, TRPM2, and TRPM8 (Harteneck et al, 2007). Importantly, CTZ has not been demonstrated to inhibit any TRP channels other than TRPM2, making this the most promising compound to proceed to in vivo studies.…”

TRPM2 channels mediate acetaminophen-induced liver damage

“…1A). Clotrimazole and ACA were previously shown to block heterologously expressed TRPM2 channels (20,21).…”