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

Petrocellis, Luciano De;Moriello, Aniello Schiano;Byun, Joon Seok;Sohn, Joo Mi;Lee, Jae Yeol;Vázquez Romero, Ana;Garrido, Maria;Messeguer, Angel;Zhang, Fang Xiong;Zamponi, Gerald W;DEPLANO, ALESSANDRO;CONGIU, CENZO;ONNIS, VALENTINA;BALBONI, GIANFRANCO;Marzo, Vincenzo Di

2015-01-01

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Abstract

Four positively charged compounds, previously shown to produce analgesic activity by interacting with prokinecitin receptor or T-type calcium channels, were tested for their ability to inhibit capsaicin-induced elevation of intracellular Ca(2+) elevation 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 8aA inhibitor. 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.