β-Arrestin biased G protein-coupled receptor ligands represent important molecular probes and may increase favorable drug action and safety as novel therapeutics. Starting from recently discovered hydroxy-substituted heterocyclic piperazine scaffolds, we have developed a series of dopamine D₂ receptor ligands with a pyrazolo[1,5-a]pyridine as secondary pharmacophore that is functionalized in position 3 by a formyl or hydroxyiminomethyl substituent. The ligands, especially the benzoxazinone 9d, were found to stimulate substantial β-arrestin-2 recruitment, while being nearly devoid of activity in a GTPγS binding assay. Investigating a new series of truncated analogs lacking a secondary pharmacophore, considerable β-arrestin-2 recruitment in the absence of G protein activation was found, when a 5-hydroxy-2H-benzo[b][1,4]oxazin-3(4H)-one was combined with an N-propyl-substituted 1,4-diazepane (15c). Although 15c displayed reduced potency compared to 9d, the dose-response curves indicate that a hydroxy-substituted heterocyclic primary pharmacophore is sufficient for the functionally selective activation of D₂R.

β-Arrestin偏倚的G蛋白偶联受体配体代表重要的分子探针，可以提高药物的作用和安全性，成为一种新型疗法。从最近发现的羟基取代的杂环哌嗪支架开始，我们开发了一系列多巴胺D ₂受体配体，其中吡唑并[1,5- a ]吡啶为二级药效基团，在位置3处被甲酰基或羟基亚氨基甲基取代基官能化。配体，尤其是苯并嗪酮9d被发现刺激β-arrestin-2大量募集，而在GTPγS结合试验中几乎没有活性。研究了一系列缺乏辅助药效团的截短的类似物，发现当5-羟基-2 H-苯并[ b ] [1,4]恶唑-3时，在没有G蛋白活化的情况下大量募集了β-arrestin-2。将（4 H）-1与N-丙基取代的1，4-二氮杂pan（15c）合并。尽管15c与9d相比显示出降低的效价，但剂量反应曲线表明，羟基取代的杂环一级药效基团足以实现D ₂ R的功能选择性激活。