新型S1P1受体激动剂Syl948抗皮肤移植排斥反应研究

金晶; 张海婧; 汪小涧; 周琬琪; 尹大力; 陈晓光

新型S1P1受体激动剂Syl948抗皮肤移植排斥反应研究

Effect of a novel selective S1P1 agonist, Syl948, on mouse skin transplantation

摘要

摘要: Syl948是通过化学合成获得的一种全新结构的选择性鞘氨醇-1-磷酸1型受体（sphingosine-1-phosphate receptor 1 ，S1P1）前药类激动剂。体外HTRF-IP1（homogeneous time-resolved fluorescence-IP1）检测显示，其活性磷酸酯形式Syl948-P对S1P1具有较强的激动活性 EC₅₀：（83±16）nmol·L^-1，而对S1P3激动作用较弱 EC₅₀：（1 026±90）nmol·L^-1，表明其具有良好的受体激动选择性。体内生物活性研究表明，单次灌胃给予SD大鼠Syl948（10 mg·kg^-1）能够显著降低动物外周血淋巴细胞水平，最大淋巴细胞降低百分率为63%，与相同剂量的阳性药芬戈莫德（fingolimod，FTY720）作用强度相当（以克分子剂量比较）。单次灌胃给予SD大鼠Syl948（10 mg·kg^-1），对大鼠心率没有明显影响，优于阳性药FTY720。每天灌胃给予小鼠Syl948（2或4 mg·kg^-1）能够显著延长小鼠皮肤移植模型中移植皮片的存活时间。上述研究结果提示，Syl948具有较强的抗皮肤移植排斥反应活性，且无减缓心率的不良反应。

Abstract: Syl948 is a synthesized selective S1P1 agonist with novel structure. HTRF-IP1 test indicated that Syl948-P, the active form of Syl948 in vitro, has strong activity against S1P1 (EC₅₀: 83±16 nmol·L^-1), but its effect on S1P3 was very weak (EC₅₀: 1 026±90 nmol·L^-1). In SD rats, oral administration of Syl948 10 mg·kg^-1 significantly decreased the peripheral blood lymphocytes (PBL), with the maximal PBL inhibition rate of 63%, which was as similar as equal dose of fingolimod (FTY720). Oral administration of Syl948 10 mg·kg^-1 had no effect on heart rate of SD rats, which was better than FTY720. Daily oral administration with Syl948 (2 or 4 mg·kg^-1) significantly prolonged the survival time of the allografts of skin slice on mice. In summary, the above results demonstrated that Syl948 has great selectivity in vitro and good activity in vivo, which indicated its potential use as an anti-rejection drug in skin transplantation.

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