Novel TRPV1 Modulators with Reduced Pungency Induce Analgesic Effects in Mice.
Novel TRPV1 Modulators with Reduced Pungency Induce Analgesic Effects in Mice.
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DOI：
10.1021/acsomega.1c05727
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发表时间：
2022-01-25
期刊：
影响因子：
4.1
通讯作者：
Shen Y
中科院分区：
文献类型：
--
作者：
Treat A;Henri V;Liu J;Shen J;Gil-Silva M;Morales A;Rade A;Tidgewell KJ;Kolber B;Shen Y
辣椒素是红辣椒中的一种化合物，是其刺激性的原因，也是瞬时受体电位阳离子通道，亚家族V，成员1（TRPV 1）的激动剂，长期以来一直被认为在高浓度下促进伤害感受器的脱敏。这导致了局部辣椒碱乳膏作为止痛剂来治疗急性和慢性疼痛的利用和实施。关键的是，辣椒碱乳膏的应用是有限的，因为辣椒碱的高刺激性，这是经历之前镇痛。为了解决这个问题，开发了新的辣椒素类似物以提供具有降低的刺激性的镇痛。本文报道的类似物增加了并显示了与先前的辣椒素样分子对TRPV 1的结构-活性关系（SAR）研究的一些差异，包括芳香族“A区”中苯酚的必要性，“B区”中的仲酰胺，以及疏水性“C区”中的修饰。这为以辣椒素为出发点的从头小分子设计提供了一个新的框架。在这项研究中，我们描述了辣椒素类似物的合成，其在体外活性的Ca 2+测定，并初步在体内辛辣和辣椒素类似物YB-11和YB-16作为镇痛剂的可行性研究。我们的研究结果表明，YB辣椒素类似物治疗的雄性和雌性小鼠表现出减少疼痛相关的行为，在自发福尔马林试验，以及减少热板试验中的热敏感性。
Capsaicin, the compound in hot chili peppers responsible for their pungency and an agonist of the transient receptor potential cation channel, subfamily V, member 1 (TRPV1), has long been known to promote the desensitization of nociceptors at high concentrations. This has led to the utilization and implementation of topical capsaicin cream as an analgesic to treat acute and chronic pain. Critically, the application of capsaicin cream is limited due to capsaicin’s high pungency, which is experienced prior to analgesia. To combat this issue, novel capsaicin analogues were developed to provide analgesia with reduced pungency. Analogues reported in this paper add to and show some differences from previous structure–activity relationship (SAR) studies of capsaicin-like molecules against TRPV1, including the necessity of phenol in the aromatic “A-region”, the secondary amide in the “B-region”, and modifications in the hydrophobic “C-region”. This provided a new framework for de novo small-molecule design using capsaicin as the starting point. In this study, we describe the synthesis of capsaicin analogues, their in vitro activity in Ca2+ assays, and initial in vivo pungency and feasibility studies of capsaicin analogues YB-11 and YB-16 as analgesics. Our results demonstrate that male and female mice treated with YB capsaicin analogues showed diminished pain-associated behavior in the spontaneous formalin assay as well as reduced thermal sensitivity in the hotplate assay.
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DOI：
10.1186/1745-9974-10-6
发表时间：
2014
期刊：
Cough (London, England)
影响因子：
--
作者：
Costanzo MT;Yost RA;Davenport PW
通讯作者：
Davenport PW
影响因子：
4
作者：
Kennedy, William R.;Vanhove, Geertrui F.;Selim, Mona M.
通讯作者：
Selim, Mona M.
影响因子：
3.3
作者：
Ma XL;Zhang FX;Dong F;Bao L;Zhang X
通讯作者：
Zhang X
DOI：
10.3390/ph9040066
发表时间：
2016-11-01
期刊：
Pharmaceuticals (Basel, Switzerland)
影响因子：
--
作者：
Chung MK;Campbell JN
通讯作者：
Campbell JN
影响因子：
7.4
作者：
Malmberg, AB;Mizisin, AP;Bley, KR
通讯作者：
Bley, KR