Abstract：
Solution phase synthesis was the first developed and the only method for peptide synthesis until the solid phase peptide synthesis (SPPS) introduced by Merrifield revolutionized the way peptides and their analogues are prepared nowadays. However, some peptides because of their chemical structure cannot be synthetized by SPPS, and the \"old school\" technique is still favorable to make them. Biphalin is a good example. It was first synthesized by Lipkowski almost 40 years ago as a dimeric analogue of enkephalin in which two tetra-amino acid fragments (Tyr-D-Ala-Gly-Phe-) are joined tail to tail by a hydrazide bridge. The synthesis of this octapeptide (Tyr-D-Ala-Gly-Phe-NH-NH ← Phe ← Gly ← D-Ala ← Tyr) and its analogues requires synthesis in solution because routine synthesis on a polymeric support is not possible. Biphalin shows high affinity at both μ and δ opioid receptors and produces a more robust spinal analgesia than morphine after intrathecal administration. Although biphalin and its analogues have been already deeply investigated, a complete description for its analgesic activity is not yet available.Here, we present a detailed procedure for the solution phase synthesis of biphalin.
摘要：
液相合成是第一个开发的，也是唯一的肽合成方法，直到Merrifield引入的固相肽合成（SPPS）彻底改变了肽及其类似物的制备方式。然而,一些肽由于其化学结构不能通过SPPS合成，而“老派”技术仍然有利于制造它们。Biphalin就是一个很好的例子。它是由Lipkowski在大约40年前首次合成的，是脑啡肽的二聚体类似物，其中两个四氨基酸片段（Tyr-D-Ala-Gly-Phe-）通过酰肼桥与尾相连。这种八肽（Tyr-D-Ala-Gly-Phe-NH-NH-NH-Phe-Gly-D-Ala-Tyr）及其类似物的合成需要在溶液中合成，因为不可能在聚合物载体上进行常规合成。鞘内给药后，Biphalin对μ和δ阿片受体均显示出高亲和力，并比吗啡产生更强大的脊髓镇痛作用。尽管已经对Biphalin及其类似物进行了深入的研究，尚未获得其镇痛活性的完整描述。这里,我们提出了一个详细的步骤，用于溶液相合成的biphalin。
