The Tunicate Metabolite 2-(3,5-Diiodo-4-methoxyphenyl)ethan-1-amine Targets Ion Channels of Vertebrate Sensory Neurons

Abstract

Marine tunicates produce defensive amino-acid-derived metabolites, including 2- (3,5-diiodo-4-methoxyphenyl)ethan-1-amine (DIMTA), but their mechanisms of action are rarely known. Using an assay-guided approach, we found that out of the many different sensory cells in the mouse dorsal root ganglion (DRG), DIMTA selectively affected low-threshold cold thermosensors. Whole-cell electrophysiology experiments using DRG cells, channels expressed in Xenopus oocytes, and human cell lines revealed that DIMTA blocks several potassium channels, reducing the magnitude of the afterhyperpolarization and increasing the baseline intracellular calcium concentration [Ca 2+ ] i of low-threshold cold thermosensors. When injected into mice, DIMTA increased the threshold of cold sensation by >3 °C. DIMTA may thus serve as a lead in the further design of compounds that inhibit problems in the cold-sensory system, such as cold allodynia and other neuropathic pain conditions.

Marine natural products

“…682 Further investigation of the biological effects of known ascidian MNPs has identied plakinidine D and 3,5-diiodo-4methoxyphenethylamine to be weak inhibitors of colony formation of Chinese hamster V79 cells, 683 with other studies identifying the latter phenethylamine analogue to also be capable of blocking several potassium channels. 684 Pyrimidine substituted variants of meridianin C were less active than the MNP at inhibiting GSK-3b but were more active in improving glucose uptake implying the presence of other signalling protein targets. 685 A single oral dose rat drug metabolism study of meridianin C has identied N/O-glucuronidation, O-sulfation and a range of hydroxylation metabolites.…”