Electrophilic N-benzylnaltrindoles as delta opioid receptor-selective antagonists.
Electrophilic N-benzylnaltrindoles as delta opioid receptor-selective antagonists.
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亲电子 N-苄基纳尔吲哚作为 δ 阿片受体选择性拮抗剂。
DOI：
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发表时间：
1995
影响因子：
7.3
通讯作者：
P. Portoghese
中科院分区：
文献类型：
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作者：
V. Korlipara;A. Takemori;P. Portoghese
N-苄基纳曲吲哚（1，BNTI）是一种有效的选择性δ 2阿片受体拮抗剂，其N-苄基被用作支架以容纳亲电子部分（异硫氰酸酯和卤代乙酰胺），以获得选择性亲和标记（2-4和8-11）。还合成了相应的乙酰胺衍生物（5-7）作为非亲电对照。o-和p-异硫氰酸酯（2和4）和卤代酰胺（8-11）是小鼠输精管（MVD）制剂中的选择性δ阿片受体拮抗剂，而Meta异构体3是δ选择性完全激动剂（IC 50 = 5 nM）。发现2和4的作用在MVD中作为时间的函数增加的事实表明耐洗组分的共价机制。间异硫氰酸酯3被发现是一个δ-选择性和不可逆的激动剂的MVD，它建议，它可能是共价结合到激动剂识别位点。在小鼠腹部牵张抗伤害感受试验中，化合物2-4和9是δ-选择性拮抗剂，但表现出比BNTI的δ 2/δ 1选择性比率。
The N-benzyl group of N-benzylnaltrindole (1, BNTI), a potent and selective delta 2 opioid receptor antagonist, was employed as a scaffold to hold electrophilic moieties (isothiocyanate and haloacetamide) in an effort to obtain selective affinity labels (2-4 and 8-11). The corresponding acetamide derivatives (5-7) also were synthesized to serve as nonelectrophilic controls. The o- and p-isothiocyanates (2 and 4) and the haloamides (8-11) were selective delta opioid receptor antagonists in the mouse vas deferens (MVD) preparations, while the meta isomer 3 was a delta-selective full agonist (IC50 = 5 nM). The fact that the effect of 2 and 4 was found to increase as a function of time in MVD suggests a covalent mechanism for the wash resistant component. The m-isothiocyanate 3 was found to be a delta-selective and irreversible agonist in the MVD, and it is suggested that it may be covalently binding to an agonist recognition site. In the mouse abdominal stretch antinociceptive assay, compounds 2-4 and 9 were delta-selective antagonists but exhibited delta 2/delta 1 selectivity ratios than that of BNTI.