Identification of Small-Molecule Positive Modulators of Calcitonin-like Receptor-Based Receptors.,ACS Pharmacology & Translational Science

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Identification of Small-Molecule Positive Modulators of Calcitonin-like Receptor-Based Receptors.
ACS Pharmacology & Translational Science ( IF 4.9 ) Pub Date : 2020-03-12 , DOI: 10.1021/acsptsci.9b00108
Erica R Hendrikse _{1,

2} , Lydia P Liew ₃ , Rebekah L Bower _{1,

2} , Muriel Bonnet ₃ , Muhammad A Jamaluddin _{1,

2} , Nicole Prodan ₁ , Keith D Richards ₁ , Christopher S Walker _{1,

2} , Garry Pairaudeau ₄ , David M Smith ₅ , Roxana-Maria Rujan ₆ , Risha Sudra ₆ , Christopher A Reynolds ₆ , Jason M Booe ₇ , Augen A Pioszak ₇ , Jack U Flanagan _{2,

3} , Michael P Hay _{2,

3} , Debbie L Hay _{1,

2}

Affiliation

Class B G protein-coupled receptors are highly therapeutically relevant but challenges remain in identifying suitable small-molecule drugs. The calcitonin-like receptor (CLR) in particular is linked to conditions such as migraine, cardiovascular disease, and inflammatory bowel disease. The CLR cannot act as a cell-surface receptor alone but rather must couple to one of three receptor activity-modifying proteins (RAMPs), forming heterodimeric receptors for the peptides adrenomedullin and calcitonin gene-related peptide. These peptides have extended binding sites across their receptors. This is one reason why there are few small-molecule ligands that can modulate these receptors. Here we describe small molecules that are able to positively modulate the signaling of the CLR with all three RAMPs but are not active at the related calcitonin receptor. These compounds were selected from a β-arrestin recruitment screen, coupled with rounds of medicinal chemistry to improve their activity. Translational potential is shown as the compounds can positively modulate cAMP signaling in a vascular cell line model. Binding experiments do not support an extracellular domain binding site; however, molecular modeling reveals potential allosteric binding sites in multiple receptor regions. These are the first small-molecule positive modulators described for the CLR:RAMP complexes.

中文翻译：

基于降钙素样受体的受体的小分子正调节剂的鉴定。

BG类蛋白偶联受体与治疗高度相关，但是在鉴定合适的小分子药物方面仍然存在挑战。降钙素样受体（CLR）特别与诸如偏头痛，心血管疾病和炎症性肠病等疾病有关。CLR不能单独充当细胞表面受体，而必须与三种受体活性修饰蛋白（RAMP）之一结合，形成肾上腺髓质素和降钙素基因相关肽的异二聚体受体。这些肽在其受体上具有延伸的结合位点。这就是为什么几乎没有小分子配体可以调节这些受体的原因之一。在这里，我们描述了能够与所有三个RAMP积极调节CLR信号传导但在相关降钙素受体上没有活性的小分子。这些化合物选自β-arrestin募集筛选，以及几轮药物化学反应以提高其活性。由于化合物可以在血管细胞系模型中积极调节cAMP信号传导，因此显示了翻译潜力。结合实验不支持细胞外结构域结合位点。然而，分子建模揭示了多个受体区域中潜在的变构结合位点。这些是针对CLR：RAMP配合物描述的第一个小分子正调节剂。然而，分子建模揭示了多个受体区域中潜在的变构结合位点。这些是针对CLR：RAMP配合物描述的第一个小分子正调节剂。然而，分子建模揭示了多个受体区域中潜在的变构结合位点。这些是针对CLR：RAMP配合物描述的第一个小分子正调节剂。

更新日期：2020-04-23

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