Synthesis of acyclic and dehydroaspartic acid analogues of Ac-Asp-Glu-OH and their inhibition of rat brain N-acetylated alpha-linked acidic dipeptidase (NAALA dipeptidase).
Synthesis of acyclic and dehydroaspartic acid analogues of Ac-Asp-Glu-OH and their inhibition of rat brain N-acetylated alpha-linked acidic dipeptidase (NAALA dipeptidase).
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Ac-Asp-Glu-OH 的无环和脱氢天冬氨酸类似物的合成及其对大鼠脑 N-乙酰化 α-连接酸性二肽酶（NAALA 二肽酶）的抑制。
DOI：
10.1021/jm00172a009
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发表时间：
1990
影响因子：
7.3
通讯作者：
Johnson,RL
中科院分区：
文献类型：
--
作者：
Subasinghe,N;Schulte,M;Chan,MY;Roon,RJ;Koerner,JF;Johnson,RL
The following structural and conformationally constrained analogues of Ac-Asp-Glu-OH (1) were synthesized: Ac-Glu-Glu-OH (2), Ac-D-Asp-Glu-OH (3), Ac-Glu-Asp-OH (4), Ac-Asp-Asp-OH (5), Ac-Asp-3-aminohexanedioic acid (6), Ac-3-amino-3-(carboxymethyl) propanoyl-Glu-OH (7), TV-succinyl-Glu-OH (8), iV-maleyl-Glu-OH (9), N-fumaryl-Glu-OH (10), andAc-AzAsp-Glu-OH (11). These analogues were evaluated for their ability to inhibit the hydrolysis of Ac-Asp-[3, 4-3/i]-Glu-OH by N-acetylated «-linked acidic dipeptidase (NAALA dipeptidase) in order to gain some insight into the structural requirements for the inhibition of this enzyme. Analogues4-6 and 9 were very weak inhibitors of NAALA dipeptidase (K¡> 40 µ), while 2, 3, and 7 with K¡ values ranging from 3.2-8.5 µ showed intermediate inhibitory activity. Themost active inhibitors of NAALA dipeptidase were compounds8, 10, and 11 with K¡ values of 0.9, 0.4, and 1.4 µ, respectively. These results suggest that the relative spacing between the side chain carboxyl and the «-carboxyl group of the C-terminal residue may be important for binding to the active site of the enzyme. They also indicate that the! torsional angle for the aspartyl residue is in the vicinity of 0.Localization1-3 and release studies4-5 suggest a role for the acidic dipeptide Ac-Asp-Glu-OH (1) in synaptic pro-cesses. Binding studies6 7which demonstrated that Ac-Asp-Glu-OH was capable of displacing radiolabeled glutamic acid from synaptic plasma membranes and elec-trophysiological studies7-13 that reported that Ac-Asp-Glu-OH exhibited excitatory effects when injected into a rat brain led many researchers to suggest a neurotran-smitter role for 1. The identification of an N-acetylated
