Understanding the functional relevance of G protein-coupled receptor (GPCR) homodimerization has been limited by the insufficient tools to assess asymmetric signaling occurring within dimers comprised of the same receptor type. We present unmatched bivalent ligands (UmBLs) to study the asymmetric function of melanocortin homodimers. UmBLs contain one agonist and one antagonist pharmacophore designed to target a melanocortin homodimer such that one receptor is occupied by an agonist and the other receptor by an antagonist pharmacophore. First-in-class biased UmBLs (BUmBLs) targeting the human melanocortin-4 receptor (hMC4R) were discovered. The BUmBLs displayed biased agonism by potently stimulating cAMP signaling (EC50 ∼ 2-6 nM) but minimally activating the β-arrestin recruitment pathway (≤55% maximum signal at 10 μM). To our knowledge, we report the first single-compound strategy to pharmacologically target melanocortin receptor allosteric signaling that occurs between homodimers that can be applied straightforwardly in vitro and in vivo to other GPCR systems.

中文翻译：

---

制定有偏向的无配二价配体（BUmBL）设计策略，以针对黑皮质素受体内的GPCR同型变构信号（cAMP超过β-Arrestin2募集）。

由于缺乏足够的工具来评估由相同受体类型组成的二聚体中发生的不对称信号传导，限制了对G蛋白偶联受体（GPCR）均二聚功能相关性的理解。我们提出了无与伦比的二价配体（UmBLs），以研究黑皮质素同二聚体的不对称功能。UmBLs包含一种激动剂和一种拮抗药效团，其设计为靶向黑皮质素同型二聚体，以使一种受体被激动剂占据，另一种受体被拮抗剂药效团占据。发现了针对人类黑皮质素4受体（hMC4R）的同类偏见性UmBLs（BUmBLs）。BUmBLs通过有效刺激cAMP信号传导（EC50〜2-6 nM），但最小程度地激活β-arrestin募集途径（在10μM时最大信号≤55％）表现出偏向性激动作用。据我们所知，