DELTA-OPIOIDMIMETIC ANTAGONISTS - PROTOTYPES FOR DESIGNING A NEW-GENERATION OF ULTRASELECTIVE OPIOID-PEPTIDES
DELTA-OPIOIDMIMETIC ANTAGONISTS - PROTOTYPES FOR DESIGNING A NEW-GENERATION OF ULTRASELECTIVE OPIOID-PEPTIDES
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DOI：
10.1007/bf03401608
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发表时间：
1995-09-01
影响因子：
5.7
通讯作者：
LAZARUS, LH
中科院分区：
文献类型：
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作者：
SALVADORI, S;ATTILA, M;LAZARUS, LH
背景资料：Tyr-Tic（1，2，3，4-四氢异喹啉-3-羧酸）和Tyr-Tic-Ala是缺乏Phe的具有δ阿片拮抗剂活性的第一种肽，基于两栖动物皮肤阿片样物质的N-末端三肽序列（Tyr-D-Xaa-Phe），Phe被认为是阿片样物质活性所必需的。材料与方法：采用Fmoc技术，以Boc-Dmt-OH或Boc-Tyr（But）-OH分别与H-L-Tic-OBut或H-D-Tic-OBut缩合，通过固相法和液相法合成Tyr和Dmt肽。结果：H-Dmt-Tic-OH具有较高的亲和性（Ki（delta）= 0.022 nM）和非凡的选择性（Ki（mu）/Ki（delta）= 150，000）; H-Dmt-Tic-Ala-OH具有Ki（δ）= 0.29 nM和δ选择性= 20，000。相对于H-Tyr-Tic-OH，亲和力和选择性分别增加8700倍和1000倍。H-Dmt-Tic-OH和H-Dmt-Tic-NH 2符合单位点受体结合模型（eta = 0.939-0.987），而H-Dmt-Tic-ol、H-Dmt-Tic-Ala-OH和H-Dmt-Tic-Ala-NH 2最适合双位点模型（eta = 0.708-0.801，F 18.9-26.0，p < 0.0001）。酰胺化使μ亲和力增加10- 100倍，并与D-Tic（2）协同作用以逆转选择性（δ-> μ）。Dmt-Tic二肽和三肽对小鼠输精管显示δ拮抗剂生物活性（K-e = 4-66 nM），在豚鼠回肠制备物中缺乏激动剂μ活性（> 10 μ M）。Dmt-Tic类似物与kappa受体在1至> 20 μ M的范围内弱相互作用。结论：Dmt-Tic阿片样肽是一类非常有效的阿片肽拮抗剂，其效力大于非阿片δ拮抗剂纳曲吲哚，并具有作为临床和治疗化合物的潜在应用。
Background: Tyr-Tic (1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid) and Tyr-Tic-Ala were the first peptides with delta opioid antagonist activity lacking Phe, considered essential for opioid activity based on the N-terminal tripeptide sequence (Tyr-D-Xaa-Phe) of amphibian skin opioids. Analogs were then designed to restrain the rotational flexibility of Tyr by the substitution of 2,6-dimethyl-L-tyrosine (Dmt).Materials and Methods: Tyr and Dmt peptides were synthesized by solid phase and solution methods using Fmoc technology or condensing Boc-Dmt-OH or Boc-Tyr(But)-OH with H-L-Tic-OBut or H-D-Tic-OBut, respectively. Peptides were purified (> 99%) by HPLC and characteristics determined by H-1-NMR, FAB-MS, melting point, TLC, and amino acid analyses.Results: H-Dmt-Tic-OH had high affinity (K-i(delta) = 0.022 nM) and extraordinary selectivity (K-i(mu)/K-i(delta) = 150,000); H-Dmt-Tic-Ala-OH had a K-i(delta) = 0.29 nM and delta selectivity = 20,000. Affinity and selectivity increased 8700- and 1000-fold relative to H-Tyr-Tic-OH, respectively. H-Dmt-Tic-OH and H-Dmt-Tic-NH2 fitted one-site receptor binding models (eta = 0.939-0.987), while H-Dmt-Tic-ol, H-Dmt-Tic-Ala-OH and H-Dmt-Tic-Ala-NH2 best fitted two-site models (eta = 0.708-0.801, F 18.9-26.0, p < 0.0001). Amidation increased mu affinity by 10- to 100-fold and acted synergistically with D-Tic(2) to reverse selectivity (delta --> mu). Dmt-Tic di- and tripeptides exhibited delta antagonist bioactivity (K-e = 4-66 nM) with mouse vas deferens and lacked agonist mu activity (> 10 mu M) in guinea-pig ileum preparations. Dmt-Tic analogs weakly interacted with kappa receptors in the 1 to > 20 mu M range.Conclusions: Dmt-Tic opioidmimetic peptides represent a highly potent class of opioid peptide antagonists with greater potency than the nonopioid delta antagonist naltrindole and have potential application as clinical and therapeutic compounds.