Persistent or chronic pain is the primary reason people seek medical care, yet current therapies are either limited in efficacy or cause intolerable side effects. Diverse mechanisms contribute to the basic phenomena of nociceptor hyperexcitability that initiates and maintains pain. Two prominent players in the modulation of nociceptor hyperexcitability are the transient receptor potential vanilloid type 1 (TRPV1) ligand-gated ion channel and the voltage-gated potassium channel, Kv7.2/3, that reciprocally regulate neuronal excitability. Across many drug development programs targeting either TRPV1 or Kv7.2/3, significant evidence has been accumulated to support these as highly relevant targets; however, side effects that are poorly separated from efficacy have limited the successful clinical translation of numerous Kv7.2/3 and TRPV1 drug development programs. We report here the pharmacological profile of 3 structurally related small molecule analogues that demonstrate a novel mechanism of action (MOA) of dual modulation of Kv7.2/3 and TRPV1. Specifically, these compounds simultaneously activate Kv7.2/3 and enable unexpected specific and potent inhibition of TRPV1. This in vitro potency translated to significant analgesia in vivo in several animal models of acute and chronic pain. Importantly, this specific MOA is not associated with any previously described Kv7.2/3 or TRPV1 class-specific side effects. We suggest that the therapeutic potential of this MOA is derived from the selective and specific targeting of a subpopulation of nociceptors found in rodents and humans. This efficacy and safety profile supports the advancement of dual TRPV1-Kv7.2/3 modulating compounds into preclinical and clinical development for the treatment of chronic pain.

中文翻译：

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双 Kv7.2/3-TRPV1 调节剂可抑制伤害感受器过度兴奋并减轻疼痛，且不会产生与目标相关的副作用。


持续性或慢性疼痛是人们寻求医疗护理的主要原因，但目前的治疗方法要么疗效有限，要么引起无法忍受的副作用。多种机制导致了引发和维持疼痛的伤害感受器过度兴奋的基本现象。调节伤害感受器过度兴奋性的两个重要参与者是瞬态受体电位香草酸 1 型 (TRPV1) 配体门控离子通道和电压门控钾通道 Kv7.2/3，它们相互调节神经元兴奋性。在许多针对 TRPV1 或 Kv7.2/3 的药物开发计划中，已经积累了重要的证据来支持这些作为高度相关的目标；然而，与疗效难以区分的副作用限制了众多 Kv7.2/3 和 TRPV1 药物开发项目的成功临床转化。我们在此报告了 3 种结构相关的小分子类似物的药理学概况，这些类似物证明了 Kv7.2/3 和 TRPV1 双重调节的新作用机制 (MOA)。具体来说，这些化合物同时激活 Kv7.2/3 并能够对 TRPV1 产生意想不到的特异性和有效抑制。这种体外效力在多种急性和慢性疼痛动物模型中转化为显着的体内镇痛作用。重要的是，这种特定的 MOA 与任何先前描述的 Kv7.2/3 或 TRPV1 类特定副作用无关。我们认为，这种 MOA 的治疗潜力源于对啮齿动物和人类中发现的伤害感受器亚群的选择性和特异性靶向。这种功效和安全性支持双 TRPV1-Kv7.2/3 调节化合物进入治疗慢性疼痛的临床前和临床开发。