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首页> 外文期刊>Journal of Medicinal Chemistry >Synthesis and Structure-Activity Relationships of an Orally Available and Long-Acting Analgesic Peptide, N~α-Amidino-Tyr-D-Arg-phe-MeβAla-OH (ADAMB)
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Synthesis and Structure-Activity Relationships of an Orally Available and Long-Acting Analgesic Peptide, N~α-Amidino-Tyr-D-Arg-phe-MeβAla-OH (ADAMB)

机译：口服有效的长效止痛肽N〜α-A基-Tyr-D-Arg-phe-MeβAla-OH（ADAMB）的合成及构效关系

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摘要

A novel dermorphin tetrapeptide N~α-amidino-Tyr-D-Arg-Phe-MeβAla-OH (ADAMB) was designed based on the structures of several dermorphin tetrapeptide analogues, including N~α-amidino-Tyr-D-Arg-Phe-Gly-OH (ADA-DER), H-Tyr-D-Arg-Phe-βAla-OH (TAPA), and H-Tyr-D-Arg-Phe-Sar-OH (DAS-DER). These parent compounds were known to show a weak oral analgesic activity in animals and/or to possess a different mechanism of analgesia from other μ-opioid peptides. Six analogues of ADAMB were also synthesized to investigate the effect on potency of N-terminal midination and N-methyl-β-alanine (MeβAla) substitution at position 4. Compounds were assessed using the tail pressure test in mice after subcutaneous and oral administration. Among the peptides tested, ADAMB showed the strongest oral antinociceptive activity, with an ED_(50) of 5.8 vs 22.2 mg/kg for morphine, as well as a 38-fold stronger activity after subcutaneous administration. ADAMB also showed long-lasting antinociceptive activity, with 50% of the maximum effect persisting in the tail pressure test at 10 h after oral administration (10 mg/kg). In contrast, orally administered morphine (80 mg/kg showed a rapid decrease of activity in the same test and its antinociceptive effect disappeared within 4 h. When the antinociceptive effect of ADAMB was compared with that of analogues possessing βAla~4 (1) or Sar~4 (2), as well as analogues with N-substitution (3-6), it was found that both the N~α-amidino substitution and the MeβAla~4 were synergistically involved in Creating ADAMB's exceptionally high antinociceptive activity.
机译：基于包括N〜α-ami胺基-Tyr-D-Arg-Phe在内的几种dermorphin四肽类似物的结构，设计了新型的吗啡四肽N〜α-ami基-Tyr-D-Arg-Phe-MeβAla-OH（ADAMB）。 -Gly-OH（ADA-DER），H-Tyr-D-Arg-Phe-βAla-OH（TAPA）和H-Tyr-D-Arg-Phe-Sar-OH（DAS-DER）。已知这些母体化合物在动物中显示出较弱的口服镇痛活性和/或具有与其他μ阿片类肽不同的镇痛机理。还合成了ADAMB的6个类似物，以研究4位上N末端酰胺化和N-甲基-β-丙氨酸（MeβAla）取代的效力。在皮下和口服给药后，使用尾压试验在小鼠中评估化合物。在测试的肽中，ADAMB显示出最强的口服抗伤害感受活性，吗啡的ED_（50）为5.8对22.2 mg / kg，皮下给药后的活性为38倍。 ADAMB还显示出持久的抗伤害感受活性，在口服给药10小时（10 mg / kg）后的尾压测试中，最大效果持续了50％。相比之下，口服吗啡（80 mg / kg）在同一试验中显示出活性的快速下降，其抗伤害作用在4 h内就消失了。将ADAMB的抗伤害作用与具有βAla〜4（1）或类似物的类似物进行比较Sar〜4（2）以及具有N取代基的类似物（3-6），发现N〜α--基取代和MeβAla〜4都协同参与了ADAMB异常高的伤害感受活性的产生。

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