Discovery of G Protein-Biased Dopaminergics with a Pyrazolo[1,5‑a]pyridine Substructure

1,4-Disubstituted aromatic piperazines
are privileged structural
motifs recognized by aminergic G protein-coupled receptors. Connection
of a lipophilic moiety to the arylpiperazine core by an appropriate
linker represents a promising concept to increase binding affinity
and to fine-tune functional properties. In particular, incorporation
of a pyrazolo­[1,5-a]­pyridine heterocyclic appendage
led to a series of high-affinity dopamine receptor partial agonists.
Comprehensive pharmacological characterization involving BRET biosensors,
binding studies, electrophysiology, and complementation-based assays
revealed compounds favoring activation of G proteins (preferably Go) over β-arrestin recruitment at dopamine D2 receptors. The feasibility to design G protein-biased partial agonists
as putative novel therapeutics was demonstrated for the representative
2-methoxyphenylpiperazine 16c, which unequivocally displayed
antipsychotic activity in vivo. Moreover, combination of the pyrazolo­[1,5-a]­pyridine appendage with a 5-hydroxy-N-propyl-2-aminotetraline unit led to balanced or G protein-biased
dopaminergic ligands depending on the stereochemistry of the headgroup,
illustrating the complex structure–functional selectivity relationships
at dopamine D2 receptors.

1,4-二取代的芳香族哌嗪，作为一种被胺能G蛋白偶联受体所识别的特权性结构基元，备受关注。通过适当连接体将亲脂性基团连接到芳基哌嗪核上，是提升结合亲和力并精调功能特性的一个极具潜力的概念。特别是，引入吡唑并[1,5-a]吡啶杂环取代基，形成了一系列高亲和力的多巴胺受体部分激动剂。涉及BRET生物传感器、结合研究、电生理学以及互补性检测的全面药理学表征揭示了有利于激活G蛋白（尤其是Go蛋白）而非β- arrestin募集的多巴胺D2受体化合物。设计G蛋白偏向性部分激动剂作为潜在的全新治疗药物的可行性得到了证实，以代表性化合物2-甲氧基苯基哌嗪16c为例，其在体内明确表现出抗精神病活性。此外，将吡唑并[1,5-a]吡啶取代基与5-羟基-N-丙基-2-氨基四氢萘单元相结合，根据头部基团的立体化学，产生了平衡或G蛋白偏向性的多巴胺受体配体，展示了在多巴胺D2受体上的复杂结构-功能选择性关系。