Synthesis toward Bivalent Ligands for the Dopamine D2 and Metabotropic Glutamate 5 Receptors

In this study, we designed and synthesized
heterobivalent ligands
targeting heteromers consisting of the metabotropic glutamate 5 receptor
(mGluR5) and the dopamine D2 receptor (D2R).
Bivalent ligand 22a with a linker consisting of 20 atoms
showed 4-fold increase in affinity for cells coexpressing D2R and mGluR5 compared to cells solely expressing D2R.
Likewise, the affinity of 22a for mGluR5 increased 2-fold
in the coexpressing cells. Additionally, 22a exhibited
a 5-fold higher mGluR5 affinity than its monovalent precursor 21a in cells coexpressing D2R and mGluR5. These
results indicate that 22a is able to bridge binding sites
on both receptors constituting the heterodimer. Likewise, cAMP assays
revealed that 22a had a 4-fold higher potency in stable
D2R and mGluR5 coexpressing cell lines than 1. Furthermore, molecular modeling reveals that 22a is
able to simultaneously bind both receptors by passing between the
TM5–TM6 interface and establishing six protein–ligand
H-bonds.

本研究中，我们设计并合成了靶向由代谢型谷氨酸受体5（mGluR5）和多巴胺D2受体（D2R）组成的异源二聚体的异双价配体。具有由20个原子组成的连接基的二元配体22a与仅表达D2R的细胞相比，在共表达D2R和mGluR5的细胞中表现出亲和力的4倍增加。同样，22a在共表达细胞中对mGluR5的亲和力也增加了2倍。此外，22a在共表达D2R和mGluR5的细胞中对mGluR5的亲和力比其单价前体21a高5倍。这些结果表明，22a能够连接构成异源二聚体的两个受体的结合位点。同样，cAMP检测揭示了22a在稳定的D2R和mGluR5共表达细胞系中的效力比1高4倍。此外，分子建模表明，22a能够通过穿越TM5-TM6界面并形成六个蛋白质-配体氢键，同时与两个受体结合。