Synthesis and biological evaluations of novel endomorphin analogues containing α-hydroxy-β-phenylalanine (AHPBA) displaying mixed μ/δ opioid receptor agonist and δ opioid receptor antagonist activities
Synthesis and biological evaluations of novel endomorphin analogues containing α-hydroxy-β-phenylalanine (AHPBA) displaying mixed μ/δ opioid receptor agonist and δ opioid receptor antagonist activities
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DOI：
10.1016/j.ejmech.2014.12.049
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发表时间：
2015-03-06
影响因子：
6.7
通讯作者：
Yu, Yongping
中科院分区：
文献类型：
--
作者：
Hu, Miao;Giulianotti, Marc A.;Yu, Yongping
合成了一系列新型内吗啡肽-1 (EM-1) 和内吗啡肽-2 (EM-2) 类似物，在不同位置掺入手性 α-羟基-β-苯丙氨酸 (AHPBA) 和/或 Dmt(1)-Tic(2)。评估了该系列的药理活性和代谢稳定性。与早期将 β-氨基酸取代为内吗啡素的研究一致，掺入 AHPBA 的多种类似物在放射性配体竞争结合测定中显示出对其和阿片受体（分别为 MOR 和 DOR）的高亲和力，并且在大鼠脑膜匀浆中表现出更高的稳定性，特别是 Dmt-Tic-(2R,3S) AHPBA-Phe-NH2（化合物 26）。脑室内（i.c.v.）给予26在小鼠55℃温水尾部撤回试验中产生抗伤害感受（ED50值（和95％置信区间）= 1.98（0.79-4.15）nmol，i.c.v.），相当于吗啡（235（1.13-5.03）nmol，i.c.v.），但证明除非选择性阿片类药物激动外，还具有 DOR 选择性拮抗作用。 26 例的镇痛作用没有自主活动或急性镇痛耐受。这类新型肽增加了先前报道的 EM 类似物的潜在治疗相关性。 (C) 2014 年由 Elsevier Masson SAS 出版。
A novel series of endomorphin-1 (EM-1) and endomorphin-2 (EM-2) analogues was synthesized, incorporating chiral alpha-hydroxy-beta-phenylalanine (AHPBA), and/or Dmt(1)-Tic(2) at different positions. Pharmacological activity and metabolic stability of the series was assessed. Consistent with earlier studies of beta-amino acid substitution into endomorphins, multiple analogues incorporation AHPBA displayed high affinity for it and opioid receptors (MOR and DOR, respectively) in radioligand competition binding assays, and an increased stability in rat brain membrane homogenates, notably Dmt-Tic-(2R,3S) AHPBA-Phe-NH2 (compound 26). Intracerebroventricular (i.c.v.) administration of 26 produced anti-nociception (ED50 value (and 95% confidence interval) = 1.98 (0.79-4.15) nmol, i.c.v.) in the mouse 55 degrees C warm-water tail-withdrawal assay, equivalent to morphine (235 (1.13-5.03) nmol, i.c.v.), but demonstrated DOR-selective antagonism in addition to non-selective opioid agonism. The antinociception of 26 was without locomotor activity or acute antinociceptive tolerance. This novel class of peptides adds to the potentially therapeutically relevant collection of previously reported EM analogues. (C) 2014 Published by Elsevier Masson SAS.