TIPP[PSI] - A HIGHLY POTENT AND STABLE PSEUDOPEPTIDE DELTA-OPIOID RECEPTOR ANTAGONIST WITH EXTRAORDINARY DELTA-SELECTIVITY
TIPP[PSI] - A HIGHLY POTENT AND STABLE PSEUDOPEPTIDE DELTA-OPIOID RECEPTOR ANTAGONIST WITH EXTRAORDINARY DELTA-SELECTIVITY
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DOI：
10.1021/jm00073a020
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发表时间：
1993-10-15
影响因子：
7.3
通讯作者：
LEMIEUX, C
中科院分区：
文献类型：
--
作者：
SCHILLER, PW;WELTROWSKA, G;LEMIEUX, C
合成了δ阿片拮抗剂H-Tyr-Tic-Phe-Phe-OH（TIPP）和H-Tyr-Tic-Phe-OH（TIP）的假肽类似物，其在Tic 2和Phe 3残基之间含有还原的肽键。在μ-、δ-和κ-受体选择性结合试验以及豚鼠回肠（GPI）和小鼠输精管（MVD）生物试验中检测了两种化合物H-Tyr-Ticpsi-[CH 2NH] Phe-Phe-OH（TIPP[psi]）和H-Tyr-Ticpsi-[CH 2NH]Phe-OH（TIP[psi]）。与它们各自的母体肽相比，两种假肽类似物在MVD测定中显示增加的δ拮抗剂效力、更高的δ受体亲和力和进一步改善的δ受体选择性。更有效的化合物TIPP[psi]显示出亚纳摩尔的Delta受体亲和力，并且与其他选择性Delta配体的直接比较显示出具有前所未有的Delta特异性（K（i）mu/K（i）delta = 10 500）。此外，该化合物对酶促降解高度稳定，并且与其他δ拮抗剂不同，显示出μ或κ拮抗剂特性。TIPP[psi]可能会在阿片类药物研究中作为药理学工具得到广泛使用。
Pseudopeptide analogues of the delta opioid antagonists H-Tyr-Tic-Phe-Phe-OH (TIPP) and H-Tyr-Tic-Phe-OH (TIP) containing a reduced peptide bond between the Tic2 and Phe3 residues were synthesized. The two compounds, H-Tyr-Ticpsi[CH2NH]Phe-Phe-OH (TIPP[psi]) and H-Tyr-Ticpsi-[CH2NH]Phe-OH (TIP[psi]), were tested in mu-, delta-, and kappa-receptor-selective binding assays and in the guinea pig ileum (GPI) and mouse vas deferens (MVD) bioassays. In comparison with their respective parent peptides, both pseudopeptide analogues showed increased delta antagonist potency in the MVD assay, higher delta receptor affinity and further improved delta receptor selectivity. The more potent compound, TIPP[psi], displayed subnanomolar delta receptor affinity and in direct comparisons with other selective delta ligands was shown to have unprecedented delta specificity (K(i)mu/K(i)delta = 10 500). Furthermore, this compound turned out to be highly stable against enzymatic degradation and, unlike other delta antagonists, showed mu or kappa antagonist properties. TIPP[psi] is likely to find wide use as a pharmacological tool in opioid research.