Synthesis and in vitro evaluation of a library of modified endomorphin 1 peptides

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• 作者：Yasuko Koda ; Mark Del Borgo ; Susanne T. Wessling ; Lawrence H. Lazarus ; Yoshio Okada ; Istvan Toth ; Joanne T. Blanchfield
• 关键词：Endomorphin 1 ; Opioid peptides ; Lipoamino acids ; Liposaccharides ; Drug delivery ; Oral peptide delivery
• 刊名：Bioorganic and Medicinal Chemistry
• 出版年：2008
• 期刊代码：9_09680896
• 类别：ch
• 出版时间：1 June 2008
• 卷：16
• 期：11
• 页码：6286-6296
• 文件大小：221 K

摘要

Endomorphin 1 (Endo-1 = Tyr-Pro-Trp-Phe-NH₂), an endogenous opioid with high affinity and selectivity for μ-opioid receptors, mediates acute and neuropathic pain in rodents. To overcome metabolic instability and poor membrane permeability, the N- and C-termini of Endo-1 were modified by lipoamino acids (Laa) and/or sugars, and 2′,6′-dimethyltyrosine (Dmt) replacement of Tyr. Analogues were assessed for μ-opioid receptor affinity, inhibition of cAMP accumulation, enzymatic stability, and permeability across Caco-2 cell monolayers. C-Terminus modification decreased receptor affinity, while N-terminus C8-Laa improved stability and permeability with slight change in receptor affinity. Dmt provided a promising lead compound: [C8Laa-Dmt[1]]-Endo-1 is nine times more stable (t_1/2 = 43.5 min), >8-fold more permeable in Caco-2 cell monolayers, and exhibits 140-fold greater μ-opioid receptor affinity (K_iμ = 0.08 nM).