Elongation of the Hydrophobic Chain as a Molecular Switch: Discovery of Capsaicin Derivatives and Endogenous Lipids as Potent Transient Receptor Potential Vanilloid Channel 2 Antagonists

Moriello Aniello Schiano; Lopez Chinarro Silvia; Novo Fernandez Olalla; Eras Jordi; Arnodeo Pietro; Canela-Garayoa Ramon; Vitale Rosa Maria; Di Marzo Vincenzo; De Petrocellis Luciano

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Elongation of the Hydrophobic Chain as a Molecular Switch: Discovery of Capsaicin Derivatives and Endogenous Lipids as Potent Transient Receptor Potential Vanilloid Channel 2 Antagonists

机译：疏水链的伸长作为分子开关：发现辣椒素衍生物和内源性脂质作为有效的瞬态受体潜在的香草型通道2拮抗剂

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The transient receptor potential vanilloid type-2 (TRPV2) protein is a nonselective Ca2+ permeable channel member of the TRPV subfamily, still considered an orphan TRP channel due to the scarcity of available selective and potent pharmacological tools and endogenous modulators. Here we describe the discovery of novel synthetic long-chain capsaicin derivatives as potent TRPV2 antagonists in comparison to the totally inactive capsaicin, the role of their hydrophobic chain, and how the structure-activity relationships of such derivatives led, through a ligand-based approach, to the identification of endogenous long-chain fatty acid ethanolamides or primary amides acting as TRPV2 antagonists. Both synthetic and endogenous antagonists exhibited differential inhibition against known TRPV2 agonists characterized by distinct kinetic profiles. These findings represent the first example of both synthetic and naturally occurring TRPV2 modulators with efficacy in the submicromolar/low-micromolar range, which will be useful for clarifying the physiopathological roles of this receptor, its regulation, and its targeting in pathological conditions.

机译：瞬时受体潜在的香草型-2（TRPV2）蛋白是TRPV亚家族的非选择性CA2 +可渗透的通道构件，仍然认为由于可用的选择性和有效的药理学工具和内源调节剂的稀缺而被认为是孤儿TRP通道。在这里，我们描述了新型合成的长链辣椒素衍生物，与完全活性的辣椒素，其疏水链的作用，以及这种衍生物的角色通过基于配体的方法的结构 - 活性关系如何实现这一衍生物的能量的TRPV2拮抗剂。，鉴定内源性的长链脂肪酸乙醇酰胺或原发性酰胺作为TRPV2拮抗剂。合成和内源性拮抗剂均表现出针对具有不同动力学谱的已知的TRPV2激动剂的差异抑制。这些发现者代表了合成和天然存在的TRPV2调节剂的第一实例，其具有亚微粒/低微摩拉范围的功效，这将是可用于澄清该受体，其调节和其在病理条件下的靶向的物理病理学作用。

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《Journal of Medicinal Chemistry》 |2018年第18期|共27页
作者
Moriello Aniello Schiano; Lopez Chinarro Silvia; Novo Fernandez Olalla; Eras Jordi; Arnodeo Pietro; Canela-Garayoa Ramon; Vitale Rosa Maria; Di Marzo Vincenzo; De Petrocellis Luciano;
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Natl Res Council CNR Inst Biomol Chem ICB Endocannabinoid Res Grp Via Campi Flegrei 34 I-80078 Pozzuoli NA Italy;

Univ Lleida Agrotecnio Dept Quim Avda Alcalde Rovira Roure 191 E-25198 Lleida Spain;

Univ Lleida Agrotecnio Dept Quim Avda Alcalde Rovira Roure 191 E-25198 Lleida Spain;

Univ Lleida Agrotecnio Dept Quim Avda Alcalde Rovira Roure 191 E-25198 Lleida Spain;

Natl Res Council CNR Inst Biomol Chem ICB Via Campi Flegrei 34 I-80078 Pozzuoli NA Italy;

Univ Lleida Agrotecnio Dept Quim Avda Alcalde Rovira Roure 191 E-25198 Lleida Spain;

Natl Res Council CNR Inst Biomol Chem ICB Via Campi Flegrei 34 I-80078 Pozzuoli NA Italy;

Natl Res Council CNR Inst Biomol Chem ICB Endocannabinoid Res Grp Via Campi Flegrei 34 I-80078 Pozzuoli NA Italy;

Natl Res Council CNR Inst Biomol Chem ICB Endocannabinoid Res Grp Via Campi Flegrei 34 I-80078 Pozzuoli NA Italy;

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正文语种 eng
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1. Elongation of the Hydrophobic Chain as a Molecular Switch: Discovery of Capsaicin Derivatives and Endogenous Lipids as Potent Transient Receptor Potential Vanilloid Channel 2 Antagonists [J] . Moriello Aniello Schiano, Lopez Chinarro Silvia, Novo Fernandez Olalla, Journal of Medicinal Chemistry . 2018,第18期

机译：疏水链的伸长作为分子开关：发现辣椒素衍生物和内源性脂质作为有效的瞬态受体潜在的香草型通道2拮抗剂
2. Novel potent antagonists of transient receptor potential channel, vanilloid subfamily member 1: Structure-activity relationship of 1,3-diarylalkyl thioureas possessing new vanilloid equivalents [J] . Suh YG, Lee YS, Min KH, Journal of Medicinal Chemistry . 2005,第18期

机译：瞬时受体电位通道的新型强效拮抗剂，类香草素亚家族成员1：具有新类香草素的1,3-二芳基烷基硫脲的构效关系
3. Structure-Activity Relationship Studies and Discovery of a Potent Transient Receptor Potential Vanilloid (TRPV1) Antagonist 4-[3-Chloro-5-[(1S)-1,2-dihydroxyethyl]-2-pyridyl]-N-[5-(trifluoromethyl)-2-pyridyl]-3,6-dihydro-2H-pyridine-1-carboxamide (V116517) as a Clinical Candidate for Pain Management [J] . Laykea Tafesse, Toshiyuki Kanemasa, Noriyuki Kurose, Journal of Medicinal Chemistry . 2014,第15期

机译：结构-活性关系研究和潜在的瞬态受体电位香草（TRPV1）拮抗剂4- [3-氯-5-[（1S）-1,2-二羟乙基] -2-吡啶基] -N- [5-（三氟甲基）-2-吡啶基] -3,6-二氢-2H-吡啶-1-羧酰胺（V116517）作为疼痛治疗的临床候选药物
4. Validation of the Transient Receptor Potential Vanilloid 6 Channel (TRPV6) as a Potential Biomarker in Ovarian Cancers [C] . Dominique Dugourd, Tyler Lutes, Christopher Rice, PEGS . 2015

机译：在卵巢癌中验证瞬态受体潜在的激素6声道（TRPV6）作为潜在的生物标志物
5. Potent derivatives of the bradykinin B2 receptor antagonist Hoe 140 containing analogues of arginine and lysine with increased hydrophobicity. [D] . Kennedy, Kevin Joseph. 1999

机译：缓激肽B2受体拮抗剂Hoe 140的强效衍生物含有精氨酸和赖氨酸的类似物，疏水性增强。
6. 2-(3-Fluoro-4-methylsulfonylaminophenyl) Propanamides as Potent Transient Receptor Potential Vanilloid 1 (TRPV1) Antagonists: Structure Activity Relationships of 2-Amino Derivatives in the N-(6-trifluoromethyl-pyridin-3-ylmethyl) C-region [O] . Myeong Seop Kim, HyungChul Ryu, Dong Wook Kang, -1

机译：2-（3-氟-4- methylsulfonylaminophenyl）丙酰胺作为有效的瞬时受体电位香草酸亚型1（TRpV1）拮抗剂：2-氨基衍生物在N-（6-三氟甲基 - 吡啶-3-基甲基）C-区域结构活性关系
7. Elongation of the Hydrophobic Chain as a Molecular Switch: Discovery of Capsaicin Derivatives and Endogenous Lipids as Potent Transient Receptor Potential Vanilloid Channel 2 Antagonists [O] . -1

机译：疏水链的伸长作为分子开关：发现辣椒素衍生物和内源性脂质作为有效的瞬态受体潜在的香草型通道2拮抗剂

Elongation of the Hydrophobic Chain as a Molecular Switch: Discovery of Capsaicin Derivatives and Endogenous Lipids as Potent Transient Receptor Potential Vanilloid Channel 2 Antagonists

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