稳定且强效的δ/μ阿片肽的合成：通过闭环复分解反应合成H-Tyr-c[D-Cys-Gly-Phe-D-Cys]-OH的类似物
Synthesis of stable and potent delta/mu opioid peptides: analogues of H-Tyr-c[D-Cys-Gly-Phe-D-Cys]-OH by ring-closing metathesis.
作者信息
Mollica Adriano, Guardiani Giovanni, Davis Peg, Ma Shou-Wu, Porreca Frank, Lai Josephine, Mannina Luisa, Sobolev Anatoli P, Hruby Victor J
机构信息
Università degli Studi G. D' Annunzio, Via dei Vestini 31, I-66013 Chieti, Italy.
出版信息
J Med Chem. 2007 Jun 28;50(13):3138-42. doi: 10.1021/jm061048b. Epub 2007 Jun 1.
Abstract
Ring-closing metathesis has emerged as a powerful tool in organic synthesis for generating cyclic structures via C-C double bond formation. Recently, it has been successfully used in peptide chemistry for obtaining cyclic molecules bridged through an olefin unit in place of the usual disulfide bond. Here, we describe this approach for obtaining cyclic olefin bridged analogues of H-Tyr-c[D-Cys-Gly-Phe-Cys]-OH. The synthesis of the new ligands was performed using the second generation Grubbs' catalyst. The resulting cis-8 (cDADAE) and trans-9 (tDADAE) were fully characterized and tested at delta, mu, and kappa opioid receptors. Also the linear precursor 13 (lDADAE) and the hydrogenated derivative 11 (rDADAE) also were tested. All the cyclic products containing a olefinic bond are slightly selective but highly active and potent for the delta and mu opioid receptors. Activity toward the kappa opioid receptors was absent or very low.
摘要
关环复分解反应已成为有机合成中通过形成碳 - 碳双键来生成环状结构的一种强大工具。最近，它已成功应用于肽化学领域，用于获得通过烯烃单元桥连的环状分子，以取代通常的二硫键。在此，我们描述了获得H-Tyr-c[D-Cys-Gly-Phe-Cys]-OH的环状烯烃桥连类似物的这种方法。新配体的合成使用第二代格拉布催化剂进行。所得的顺式 - 8（cDADAE）和反式 - 9（tDADAE）经过了全面表征，并在δ、μ和κ阿片受体上进行了测试。线性前体13（lDADAE）和氢化衍生物11（rDADAE）也进行了测试。所有含有烯键的环状产物对δ和μ阿片受体具有轻微的选择性，但活性和效力都很高。对κ阿片受体则没有活性或活性非常低。
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