Opiate aromatic pharmacophore structure-activity relationships in CTAP analogues determined by topographical bias, two-dimensional NMR, and biological activity assays
Opiate aromatic pharmacophore structure-activity relationships in CTAP analogues determined by topographical bias, two-dimensional NMR, and biological activity assays
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DOI：
10.1021/jm9900218
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发表时间：
2000-02-24
影响因子：
7.3
通讯作者：
Hruby, VJ
中科院分区：
文献类型：
--
作者：
Bonner, GG;Davis, P;Hruby, VJ
通过固相肽合成制备高度μ-阿片受体选择性拮抗剂CTAP（H-D-Phe-c[Cys-Tyr-D-Trp-Arg-Thr-Pen]-Thr-NH 2，1）的拓扑结构限制的类似物。用构象偏向的苯丙氨酸或色氨酸的β-甲基衍生物（2 R，3R; 2 R，3S; 2S，3R; 2S，3S）替换D-Phe残基产生显示出广泛不同类型的生物活性的肽。为了将观察到的这些类似物的生物活性与它们的结构相关联，进行了二维H-1 NMR和分子建模。与在MVD生物测定中基本上是具有弱δ激动剂活性的纯μ拮抗剂的母体（1）不同，含有非对映体β-MePhe（1）的肽通过含有（2 R，3R）的异构体2同时表现出δ激动剂和μ拮抗作用;通过含有（2 R，3S）的异构体3表现出μ拮抗作用;通过含有（2S，3R）的异构体4表现出弱μ激动作用;和含（2S，3S）异构体5的δ激动作用。将β-MeTrp异构体掺入位置1导致作为μ拮抗剂（2 R，3R），8;（2 R，3S），9或基本上无活性（
Topographically constrained analogues of the highly mu-opioid-receptor-selective antagonist CTAP (H-D-Phe-c[Cys-Tyr-D-Trp-Arg-Thr-Pen]-Thr-NH2, 1) were prepared by solid-phase peptide synthesis. Replacement of the D-Phe residue with conformationally biased beta-methyl derivatives of phenylalanine or tryptophan (2R,3R; 2R,3S; 2S,3R; 2S,3S) yielded peptides that displayed widely varying types of biological activities. In an effort to correlate the observed biological activities of these analogues with their structures, two-dimensional H-1 NMR and molecular modeling was performed. Unlike the parent (1), which is essentially a pure mu antagonist with weak delta agonist activities in the MVD bioassay, the diastereomeric beta-MePhe(1)-containing peptides exhibited simultaneous delta agonism and mu antagonism by the (2R,3R)-containing isomer 2; mu antagonism by the (2R,3S)-containing isomer 3; weak mu agonism by the (2S,3R)-containing isomer 4; and delta agonism by the (2S,3S)-containing isomer 5. Incorporation of beta-MeTrp isomers into position 1 led to peptides that were mu antagonists (2R,3R), 8; (2R,3S), 9, or essentially inactive (