Caged Capsaicins: New Tools for the Examination of TRPV1 Channels in Somatosensory Neurons

The vanilloid capsaicin, N‐(4‐hydroxy‐3‐methoxybenzyl)‐8‐methylnon‐6‐enamide, is the pungent ingredient of chili peppers and is used in pain research as an activating ligand of heat‐sensitive transduction channels in nociceptive neurons. Here we describe the synthesis and application of two capsaicin derivatives modified at the hydroxy function of the vanillyl motif: α‐carboxy‐4,5‐dimethoxy‐2‐nitrobenzyl‐caged (CDMNB‐caged) capsaicin and {7‐[bis(carboxymethyl)amino]coumarin‐4‐yl}methoxycarbonyl‐caged (BCMACMOC‐caged) capsaicin. These compounds show dramatically reduced pungency, but release active capsaicin upon irradiation with UV light. CDMNB‐caged capsaicin can be used to perform concentration‐jump experiments, while BCMACMOC‐caged capsaicin is membrane‐impermeant and can be applied selectively to the intracellular or extracellular sides of a plasma membrane. Both compounds can serve as valuable research tools in pain physiology. Light flashes and chili peppers. Extra‐ and intracellular concentration jumps of the vanilloid capsaicin can be achieved by photolysis of the newly developed α‐carboxy‐4,5‐dimethoxy‐2‐nitrobenzyl‐ and {7‐[bis(carboxymethyl)amino]coumarin‐4‐yl}methoxycarbonyl‐caged capsaicins. These phototriggers are powerful tools for the kinetic analysis of capsaicin receptor channels (TRPV1) and for study of the asymmetry of capsaicin action on these channels.