Faculty of Pharmacy, C. V. Raman Global University, Mahura, Bhubaneswar, 752054, Odisha, India.
Department of Pharmaceutical Chemistry, Institute of Pharmacy & Technology, Salipur, Cuttack, 754202, Odisha, India.
Curr Top Med Chem. 2024;24(28):2431-2446. doi: 10.2174/0115680266288509240422112839.
Sphingosine 1-phosphate (S1P) is extensively researched as a lysophospholipid and is crucial in various physiological and pathological processes. It achieves this via signalling through five different subtypes of G protein-coupled receptors (GPCRs), namely S1PR1 to S1PR5. S1PR modulators possess the ability to traverse the blood-brain barrier, potentially leading to direct actions within the Central Nervous System (CNS). S1PR modulators specifically bind to receptors located on the surface of naive and central memory lymphocytes, causing these cells to be trapped or confined within the lymph node. The investigation of the S1P pathway has resulted in the approval of three S1PR modulators, namely fingolimod, siponimod, and ozanimod, as medications for the treatment of patients suffering from Multiple Sclerosis (MS). Additionally, new S1PR modulators, such as ponesimod and etrasimod, are currently being developed and tested in clinical trials. Research on the creation of S1P modulators in neurodegenerative illnesses is ongoing as scientists continue to explore novel possibilities for selective S1P modulators. This study provides a concise overview of sphingolipid metabolism, the mechanism by which S1P receptors are affected, and the structural characteristics of several small molecule S1P modulators, with a particular focus on their structure-activity connections.
鞘氨醇 1-磷酸（S1P）作为一种溶血磷脂备受研究，在多种生理和病理过程中起着关键作用。它通过与五种不同亚型的 G 蛋白偶联受体（GPCR），即 S1PR1 到 S1PR5 进行信号传递来实现这一点。S1PR 调节剂具有穿透血脑屏障的能力，有可能在中枢神经系统（CNS）内直接发挥作用。S1PR 调节剂特异性结合位于幼稚和中央记忆淋巴细胞表面的受体，导致这些细胞被困或局限在淋巴结内。对 S1P 途径的研究导致了三种 S1PR 调节剂的批准，即芬戈莫德、西尼莫德和奥扎尼莫德，作为治疗多发性硬化症（MS）患者的药物。此外，新的 S1PR 调节剂，如泊尼莫德和埃特拉莫德，目前正在临床试验中进行开发和测试。科学家们一直在探索选择性 S1P 调节剂的新可能性，因此针对神经退行性疾病中 S1P 调节剂的研究仍在继续。本研究简要概述了鞘脂代谢、S1P 受体受影响的机制以及几种小分子 S1P 调节剂的结构特征，特别关注了它们的结构-活性关系。
