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

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• 作者：Luciano De Petrocellis^a ; ^{luciano.depetrocellis@icb.cnr.it" class="auth_mail" title="E-mail the corresponding author} ; Aniello Schiano Moriello^a ; Joon Seok Byun^b ; Joo Mi Sohn^b ; Jae Yeol Lee^b ; Ana Vá ; zquez-Romero^c ; Maria Garrido^c ; Angel Messeguer^c ; Fang-Xiong Zhang^d ; Gerald W. Zamponi^d ; Alessandro Deplano^e ; Cenzo Congiu^e ; Valentina Onnis^e ; Gianfranco Balboni^e ; ^{gbalboni@unica.it" class="auth_mail" title="E-mail the corresponding author} ; Vincenzo Di Marzo^a ; ^{vdimarzo@icb.cnr.it" class="auth_mail" title="E-mail the corresponding author}
• 关键词：TRPV1 receptor ; TRPM8 receptor ; Open-pore inhibitors ; Prokineticin receptors ; Calcium channel assay
• 刊名：Pharmacological Research
• 出版年：2015
• 出版时间：September 2015
• 年：2015
• 卷：99
• 期：Complete
• 页码：362-369
• 全文大小：1216 K

文摘

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.