Rational drug design and synthesis of a highly selective nonpeptide delta-opioid agonist, (4aS*,12aR*)-4a-(3-hydroxyphenyl)-2-methyl- 1,2,3,4,4a,5,12,12a-octahydropyrido[3,4-b]acridine (TAN-67).
Rational drug design and synthesis of a highly selective nonpeptide delta-opioid agonist, (4aS*,12aR*)-4a-(3-hydroxyphenyl)-2-methyl- 1,2,3,4,4a,5,12,12a-octahydropyrido[3,4-b]acridine (TAN-67).
复制标题
高选择性非肽 δ-阿片受体激动剂 (4aS*,12aR*)-4a-(3-羟基苯基)-2-甲基- 1,2,3,4,4a,5,12,12a 的合理药物设计和合成
DOI：
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发表时间：
1998
影响因子：
1.7
通讯作者：
T. Endoh
中科院分区：
文献类型：
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作者：
Hiroshi Nagase;K. Kawai;Jun Hayakawa;Hisanori Wakita;A. Mizusuna;H. Matsuura;C. Tajima;Yuko Takezawa;T. Endoh
我们为阿片受体设计了高选择性的非肽激动剂。基于该领域的“信息-地址”概念和辅助位点假说，合成了一类新的杂环融合八氢异喹啉衍生物。其中一种化合物[(4aS*,12aR*)-4a-（3-羟基苯基）-2-甲基-1,2,3,4,4a, 5,12,12a -八氢吡啶[3,4-b]吖啶，TAN-67(2)]在豚鼠大脑中对δ -阿片受体（Ki = 1.12 nM）具有高选择性，对mu-阿片受体的亲和力降低2070倍，对kappa-阿片受体的亲和力降低1600倍。TAN-67是一种有效的阿片受体激动剂，在小鼠输精管实验中，其IC50值为6.61 nM，被纳曲多（NTI）逆转（Ke = 0.21）。此外，在小鼠醋酸腹部收缩实验中，皮下给药后的TAN-67显示出抗痛感活性，这种活性被NTI （delta 1-和delta 2-拮抗剂）和7-苄基二醛曲酮（delta 1-拮抗剂）拮抗，但不被钠三苯（delta 2-拮抗剂）拮抗。这种系统适用的非肽激动剂将有助于阐明阿片受体的药理学性质。
We designed highly selective non-peptide agonists for the delta-opioid receptor. On the basis of the "message-address" concept in this field and the accessory site hypothesis, a novel class of heterocycle-fused octahydroisoquinoline derivatives were synthesized. One of these compounds [(4aS*,12aR*)-4a-(3-hydroxyphenyl)-2-methyl-1,2,3,4,4a,5,12, 12a -octahydropyrido[3,4-b]acridine, TAN-67 (2)] showed high selectivity for the delta-opioid receptor (Ki = 1.12 nM) in guinea-pig cerebrum with a 2070-fold lower affinity for the mu-opioid receptor and a 1600-fold lower affinity for the kappa-opioid receptor. TAN-67 was a potent delta-opioid receptor agonist with an IC50 value of 6.61 nM in the mouse vas deferens assay that was reversed by naltrindole (NTI) (Ke = 0.21). Moreover, TAN-67 was shown to have antinociceptive activity following subcutaneous administration in the mouse acetic acid abdominal constriction assay that was antagonized by NTI (delta 1- and delta 2-antagonist) and 7-benzylidinenaltrexone (delta 1-antagonist), but not by naltriben (delta 2-antagonist). This systemically applicable non-peptide agonist will be useful for elucidating the pharmacological properties of the delta-opioid receptor.