Inhibitory effect of positively charged triazine antagonists of prokineticin receptors on the transient receptor vanilloid type-1 (TRPV1) channel

Four positively charged compounds, previously shown to produce analgesic activity by interacting with prokineticin receptor or T-type calcium channels, were tested for their ability to inhibit capsaicin-induced elevation of intracellular Ca2+ in HEK-293 cells stably transfected with the human recombinant TRPV1, with the goal of identifying novel TRPV1 open-pore inhibitors. KYS-05090 showed the highest potency as a TRPV1 antagonist, even higher than that of the open-pore triazine inhibitor 8aA. The latter showed quite remarkable agonist/desensitizer activity at the rat recombinant TRPM8 channel. The activity of KYS-05090 and the other compounds was selective because none of these compounds was able to modulate the rat TRPA1 channel. Open-pore inhibitors of TRPV1 may be a new class of multi-target analgesics with lesser side effects, such as loss of acute pain sensitivity and hyperthermia, than most TRPV1 antagonists developed so far.

Four positively charged compounds previously shown to produce analgesic activity by interacting with prokineticin receptors or T-type calcium channels, inhibited capsaicin-induced and TRPV1-mediated elevation of intracellular Ca2+ in HEK-293 (left). KYS-05090 showed the highest potency as a TRPV1 antagonist, even higher than that the open-pore triazine TRPV1 inhibitor, 8aA. Electrophysiological experiments (right) showed that TRPV1-positive mouse sensory neurons exhibit significantly reduced capsaicin-evoked currents after pre-incubation with KYS-05090.155