Evaluation of the Dmt-Tic pharmacophore:: Conversion of a potent δ-opioid receptor antagonist into a potent δ agonist and ligands with mixed properties
Evaluation of the Dmt-Tic pharmacophore:: Conversion of a potent δ-opioid receptor antagonist into a potent δ agonist and ligands with mixed properties
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DOI：
10.1021/jm010449i
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发表时间：
2002-01-31
影响因子：
7.3
通讯作者：
Lazarus, LH
中科院分区：
文献类型：
--
作者：
Balboni, G;Guerrini, R;Lazarus, LH
制备了 2',6'-二甲基-L-酪氨酸 (Dmt)-1,2,3,4-四氢异喹啉-3-羧酸 (Tic) 药效团的类似物，以测试阿片肽中需要“间隔基”和第三个芳香中心才能将 δ-拮抗剂转化为具有 δ-激动剂或具有混合 δ-拮抗剂/μ-激动剂特性的配体的假设。通过改变间隔基长度[无、NH-CH2、NH-CH2-CH2、Gly-NH-CH2]和C端芳香核[1H-苯并咪唑-2-基、苯基(Ph)和苄基]，获得了具有高δ和μ阿片受体亲和力的强效δ激动剂和双功能化合物：C端修饰主要影响μ阿片受体亲和力，最大程度增加相对于原型 δ 拮抗剂 H-Dmt-Tic-NH2 提高了 1700 倍，并且生物活性有所不同。在没有间隔基 (1) 的情况下，该类似物表现出双重 δ 激动作用 (pEC(50), 7.28) 和 δ 拮抗作用 (pA(2), 7.90)。 H-Dmt-Tic-NH-CH2-1H-苯并咪唑-2-基 (Bid) (2) 成为高效 δ 激动剂 (pEC(50), 9.90)，略高于 deltorphin C (pEC(50), 9.56)，具有 mu 激动作用 (pE(50), 7.57)，而H-Dmt-Tic-Gly-NH-CH2-Bid (4) 保留了有效的 δ 拮抗作用 (pA2, 9.0)，但 mu 激动作用要低一个数量级。类似地，H-Dmt-Tic-Gly-NH-Ph (5) 具有几乎相同的高 mu 激动作用 (pEC(50)，8.52) 和 mu 激动作用 (pEC(50)，-8.59)，而其间隔基更长的单个亚甲基的 H-Dmt-TicGly-NH-CH2-Ph (6) 表现出有效的 δ 拮抗作用。 (pA2, 9.25) 和非常高的 mu 激动作用 (pEC(50), 8.57)。这些数据证实，Dmt-Tic药效团和第三个芳香核之间的距离是将Dint-Tic从高效δ-拮抗剂转化为强效δ-激动剂或具有混合δ-和μ-阿片性质的配体的重要标准。
Analogues of the 2',6'-dimethyl-L-tyrosine (Dmt)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (Tic) pharmacophore were prepared to test the hypothesis that a "spacer" and a third aromatic center in opioid peptides are required to convert a delta-antagonist into ligands with delta-agonist or with mixed delta-antagonist/mu-agonist properties. Potent delta-agonists and bifunctional compounds with high delta- and mu-opioid receptor affinities were obtained by varying the spacer length [none, NH-CH2, NH-CH2-CH2, Gly-NH-CH2] and C-terminal aromatic nucleus [1H-benzimidazole-2-yl, phenyl (Ph) and benzyl groups]: C-terminal modification primarily affected,mu-opioid receptor affinities, which increased maximally 1700-fold relative to the prototype delta-antagonist H-Dmt-Tic-NH2 and differentially modified bioactivity. In the absence of a spacer (1), the analogue exhibited dual delta-agonism (pEC(50), 7.28) and delta-antagonism (pA(2), 7.90). H-Dmt-Tic-NH-CH2-1H-benzimidazol-2-yl (Bid) (2) became a highly potent delta-agonist (pEC(50), 9.90), slightly greater than deltorphin C (pEC(50), 9.56), with mu-agonism (pE(50), 7.57), while H-Dmt-Tic-Gly-NH-CH2-Bid (4) retained potent delta-antagonism, (pA2, 9.0) but with an order of magnitude less mu-agonism. Similarly, H-Dmt-Tic-Gly-NH-Ph (5) had nearly equivalent high mu-agonism (pEC(50), 8.52) and mu-agonism (pEC(50), -8.59), while H-Dmt-TicGly-NH-CH2-Ph (6) whose spacer was longer by a single methylene group exhibited potent delta-antagonism. (pA2, 9.25) and very high mu-agonism (pEC(50), 8.57). These data confirm that the distance between the Dmt-Tic pharmacophore and a third aromatic nucleus is an important criterion in converting Dint-Tic from a highly potent delta-antagonist into a potent delta-agonist or into ligands with mixed delta- and,mu-opioid properties.