Endomorphin 1[脧脧] and endomorphin 2[脧脧], endomorphins analogues containing a reduced (CH₂NH) amide bond between Tyr¹ and Pro², display partial agonist potency but

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• 作者：Zhao ; Qian-Yu ; Chen ; Qiang ; Yang ; Ding-Jian ; Feng ; Yun ; Long ; Yuan ; Wang ; Peng ; Wang ; Rui
• 关键词：Endomorphins ; Analogues ; Reduced amide bond ; Antinociception ; Intracebroventricular ; Tail-flick ; Formalin-model
• 刊名：Life Sciences
• 出版年：2005
• 期刊代码：62_00243205
• 类别：imm
• 出版时间：July 22, 2005
• 卷：77
• 期：10
• 页码：1155-1165
• 文件大小：174 K

摘要

Endomorphin 1 (EM1) and endomorphin 2 (EM2) are highly potent and selective μ-opioid receptor agonists and have significant antinociceptive action. In the μ-selective pocket of endomorphins (EMs), Pro² residue is a spacer and directs the Tyr¹ and Trp³/Phe³ side chains into the required orientation. The present work was designed to substitute the peptide bond between Tyr¹ and Pro² of EMs with a reduced (CH₂NH) bond and study the agonist potency and antinociception of EM1[ψ] (Tyr[ψ(CH₂NH)]Pro-Trp-Phe-NH₂) and EM2[ψ] (Tyr[ψ(CH₂NH)]Pro-Phe-Phe-NH₂). Both EM1[ψ] and EM2[ψ] are partial μ opioid receptor agonists showing significant loss of agonist potency in GPI assay. However, EMs[ψ] exhibited potent supraspinal antinociceptive action in vivo. In the mice tail-flick test, EMs[ψ] (1, 5, 10 nmol/mouse, i.c.v.) produced potent and short-lasting antinociception in a dose-dependent and naloxone (1 mg/kg) reversed manner. At the highest dose of 10 nmol, the effect of EM2[ψ] was prolonged and more significant than that of EM2. In the rat model of formalin injection induced inflammatory pain, EMs[ψ] (0.1, 1, 10 nmol/rat, i.c.v.), like EMs, exerted transient but not dose-dependent antinociception. These results suggested that in the μ-selective pocket of EMs, the rigid conformation induced by the peptide bond between Tyr¹ and Pro² is essential to regulate their agonist properties at the μ opioid receptors. However, the increased conformational flexibility induced by the reduced (CH₂NH) bond made less influence on their antinociception.