含2',6'-二甲基-L-酪氨酸和吡嗪酮环平台的阿片样物质模拟物的设计与合成。
Design and synthesis of opioidmimetics containing 2',6'-dimethyl-L-tyrosine and a pyrazinone-ring platform.
作者信息
Shiotani Kimitaka, Li Tingyou, Miyazaki Anna, Tsuda Yuko, Yokoi Toshio, Ambo Akihiro, Sasaki Yusuke, Bryant Sharon D, Lazarus Lawrence H, Okada Yoshio
机构信息
The Graduate School of Food and Medicinal Sciences, Kobe Gakuin University, Nishi-ku, Kobe 651-2180, Japan.
出版信息
Bioorg Med Chem Lett. 2007 Nov 1;17(21):5768-71. doi: 10.1016/j.bmcl.2007.08.058. Epub 2007 Aug 28.
Abstract
Twelve 2',6'-dimethyl-L-tyrosine (Dmt) analogues linked to a pyrazinone platform were synthesized as 3- or 6-[H-Dmt-NH(CH(2))(n)],3- or 6-R-2(1H)-pyrazinone (n=1-4). 3-[H-Dmt-NH-(CH(2))(4)]-6-beta-phenethyl-5-methyl-2(1H)-pyrazinone 11 bound to mu-opioid receptors with high affinity (K(i)mu=0.13 nM; K(i)delta/K(i)mu=447) with mu-agonism (GPI IC(50)=15.9 nM) and weak delta-antagonism (MVD pA(2)=6.35). Key factors affecting opioid affinity and functional bioactivity are the length of the aminoalkyl chain linked to Dmt and the nature of the R residue. These data present a simplified method for the formation of pyrazinone opioidmimetics and new lead compounds.
摘要
合成了12种与吡嗪酮平台相连的2',6'-二甲基-L-酪氨酸（Dmt）类似物，其结构为3-或6-[H-Dmt-NH(CH₂)(n)]-3-或6-R-2(1H)-吡嗪酮（n = 1 - 4）。3-[H-Dmt-NH-(CH₂)₄]-6-β-苯乙基-5-甲基-2(1H)-吡嗪酮11以高亲和力（Kᵢμ = 0.13 nM；Kᵢδ/Kᵢμ = 447）与μ-阿片受体结合，具有μ-激动作用（GPI IC₅₀ = 15.9 nM）和弱δ-拮抗作用（MVD pA₂ = 6.35）。影响阿片类亲和力和功能生物活性的关键因素是与Dmt相连的氨基烷基链的长度以及R残基的性质。这些数据提供了一种形成吡嗪酮类阿片模拟物和新先导化合物的简化方法。
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