Fenoprofen—An Old Drug Rediscovered as a Biased Allosteric Enhancer for Melanocortin Receptors,ACS Chemical Neuroscience

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Fenoprofen—An Old Drug Rediscovered as a Biased Allosteric Enhancer for Melanocortin Receptors
ACS Chemical Neuroscience ( IF 4.1 ) Pub Date : 2018-08-31 00:00:00 , DOI: 10.1021/acschemneuro.8b00347
Xiao-Chen Yuan _{1,

2} , Ya-Xiong Tao ₂

Affiliation

It is time-consuming and costly to bring new drugs to market, making it necessary and urgent to exploit existing drugs for new uses. Recently, fenoprofen was demonstrated as an allosteric modulator at melanocortin receptors (MCRs), although the exact mode of action has not been clarified. MCRs regulate multiple functions, including pigmentation, adrenal steroidogenesis, inflammation, energy homeostasis, and exocrine gland secretion. In this study, we showed that fenoprofen failed to displace the orthosteric agonist Nle⁴-d-Phe⁷-α-melanocyte stimulating hormone from binding to MC3-5R while possessing positive allosteric modulator activities at these receptors. In addition, fenoprofen induced biased signaling at MC3-5R, as it selectively activated ERK1/2 cascade but not the canonical cAMP signaling. Notably, fenoprofen stimulated biased signaling at MC3-5R, but not at MC1R, hence acting selectively among this highly conserved family of receptors. Moreover, PAM activity and biased signaling induced by fenoprofen were observed not only at wild-type but also at naturally occurring mutant MC3Rs, suggesting that this biased allosteric enhancer action might constitute as novel therapeutic opportunity for obese patients harboring these mutations. Our study might guide novel therapeutic applications for repurposing current drugs or designing new drugs combining allosteric and biased properties.

中文翻译：

非诺洛芬（Fenoprofen）—一种重新发现的老药物，可作为黑皮质素受体的偏向变构促进剂

将新药推向市场既耗时又昂贵，这使得迫切需要开发现有药物以用于新用途。最近，尽管尚未阐明确切的作用方式，但已证明非诺洛芬是一种在黑皮质素受体（MCRs）上的变构调节剂。MCR调节多种功能，包括色素沉着，肾上腺类固醇生成，炎症，能量稳态和外分泌腺分泌。在这项研究中，我们表明非诺洛芬未能取代正构激动剂Nle ⁴ - d -Phe ⁷-α-黑素细胞刺激激素与MC3-5R结合，同时在这些受体上具有积极的变构调节活性。此外，非诺洛芬在MC3-5R诱导有偏的信号传导，因为它选择性激活ERK1 / 2级联反应，但不激活典型的cAMP信号传导。值得注意的是，Fenoprofen刺激了MC3-5R而不是MC1R的偏向信号传导，因此在这个高度保守的受体家族中选择性发挥作用。此外，不仅在野生型而且在天然存在的突变MC3Rs上都观察到了由fenoprofen诱导的PAM活性和偏向信号转导，这表明这种偏向变构增强剂作用可能构成具有这些突变的肥胖患者的新治疗机会。

更新日期：2018-08-31

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