DAMGO ([D-Ala², N^α-MePhe⁴, Gly⁵-ol]-enkephalin), a high-efficacy µ-opioid receptor agonist, as a tool compound, is extensively used in the preclinical analgesia studies. Due to the large amount of DAMGO required in the research and the high market price, we developed a simple and efficient solid-phase synthesis method. DAMGO has a special Gly-ol residue at C terminus, its attachment to the resin is a challenge. We chose 2-chlorotritylchloride resin as the solid support, and explored two loading methods, an amino loading method followed by a finally N-O exchange after cleavage, and a direct hydroxyl loading method. Although each has its own drawbacks, both methods obtained good yields. The direct hydroxyl loading method is more convenient and can be achieved on the gram-scale with an overall 40% yield. The synthesized DAMGO was characterized by HPLC and mass spectrometry, and GPI functional assay was further used to confirm the biological effect.

DAMGO ([D-Ala ² , N ^α -MePhe ⁴ , Gly ⁵ -ol]-脑啡肽), 一种高效µ-阿片受体激动剂作为一种工具化合物，广泛应用于临床前镇痛研究。由于研究中需要大量的DAMGO且市场价格高昂，我们开发了一种简单高效的固相合成方法。DAMGO 在 C 端有一个特殊的 Gly-ol 残基，它与树脂的连接是一个挑战。我们选择了2-氯三苯甲基氯树脂作为固相载体，探索了两种负载方法，一种是氨基负载法，裂解后最后进行NO交换，另一种是直接羟基负载法。尽管每种方法都有其自身的缺点，但两种方法都获得了良好的收益。直接羟基负载方法更方便，可以在克级实现，总收率为 40%。合成的 DAMGO 通过 HPLC 和质谱法表征，