G-protein coupled receptors (GPCRs) exist in an equilibrium of multiple conformational states, including different active states, which depend on the nature of the bound ligand. In consequence, different conformational states can initiate specific signal transduction pathways. The study identified compound 7e, which acts as a potent 5-hydroxytryptamine type 6 receptor (5-HT₆R) neutral antagonist at Gs and does not impact neurite growth (process controlled by Cdk5). MD simulations highlighted receptor conformational changes for 7e and inverse agonist PZ-1444. In cell-based assays, neutral antagonists of the 5-HT₆R (7e and CPPQ), but not inverse agonists (SB-258585, intepirdine, PZ-1444), displayed glioprotective properties against 6-hydroxydopamine-induced and doxorubicin-induced cytotoxicity. These suggest that targeting the activated conformational state of the 5-HT₆R with neutral antagonists implicates the protecting properties of astrocytes. Additionally, 7e prevented scopolamine-induced learning deficits in the novel object recognition test in rats. We propose 7e as a probe for further understanding of the functional outcomes of different states of the 5-HT₆R.

中文翻译：

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咪唑并吡啶基于5-HT ₆受体中性拮抗剂：的影响Ñ ¹苄基和Ñ ¹上不同的受体-苯片段构象状态

G蛋白偶联受体（GPCR）以多种构象状态（包括不同的活性状态）的平衡状态存在，这取决于结合的配体的性质。结果，不同的构象状态可以启动特定的信号转导途径。该研究确定了化合物7e，该化合物在Gs上充当有效的5-羟基色胺6型受体（5-HT ₆ R）中性拮抗剂，并且不影响神经突生长（受Cdk5控制）。MD模拟强调了7e和反向激动剂PZ-1444的受体构象变化。在基于细胞的测定中，5-HT ₆ R（7e和CPPQ），但没有反向激动剂（SB-258585，intepirdine，PZ-1444），对6-羟基多巴胺诱导和阿霉素诱导的细胞毒性具有胶质保护特性。这些表明，用中性拮抗剂靶向5-HT ₆ R的活化构象状态暗示了星形胶质细胞的保护特性。此外，在大鼠的新型物体识别测试中，7e预防了东pol碱引起的学习缺陷。我们建议7e作为进一步理解5-HT ₆ R不同状态的功能结果的探针。