Department of Pathophysiology, Faculty of Medicine, Medical University, Sofia, 1431, Bulgaria.
Amino Acids. 2013 Oct;45(4):983-8. doi: 10.1007/s00726-013-1555-4. Epub 2013 Jul 13.
Aiming to develop more potent analgesic substances a new series of hexapeptides containing β(2)-tryptophan analogues was synthesized. The Trp in position 4 and 5, respectively in Ac-Arg-Phe-Met-Trp-Met-Lys-NH2 (opioid receptor antagonist) and Ac-Arg-Tyr-Tyr-Arg-Trp-Lys-NH2 (highly potent and selective NOP-receptor agonist) was substituted by the (S)-2-(1-methyl-1H-indol-3-yl)propionic residue or the (S)-2-(5-methoxy-1H-indol-3-yl)propionic residue. The analgesic effect of the four newly synthesized compounds has been evaluated in male Wistar rats by PP- and HP tests and compared to the native templates. Further estimation of the mechanisms of action of each compound was achieved using specific antagonists-naloxone for opioid and JTC801 for the NOP receptor. Replacement of Trp with β(2)-tryptophan analogues in 4th position (Ac-Arg-Phe-Met-Trp-Met-Lys-NH2) led to increased and longer lasting analgesic effect. The results obtained permit us to assume that both opioid and NOP receptors take part in the newly synthesized compounds analgesic effects.
为了开发更有效的镇痛物质，我们合成了一系列含有β(2)-色氨酸类似物的六肽。在 Ac-Arg-Phe-Met-Trp-Met-Lys-NH2（阿片受体拮抗剂）和 Ac-Arg-Tyr-Tyr-Arg-Trp-Lys-NH2（高活性和选择性 NOP 受体激动剂）中，分别位于 4 位和 5 位的 Trp 被（S）-2-（1-甲基-1H-吲哚-3-基）丙酸残基或（S）-2-（5-甲氧基-1H-吲哚-3-基）丙酸残基取代。通过 PP-和 HP 试验，在雄性 Wistar 大鼠中评估了这四种新合成化合物的镇痛作用，并与天然模板进行了比较。进一步使用特定的拮抗剂-纳洛酮（阿片受体）和 JTC801（NOP 受体）评估了每种化合物作用机制。在 4 位（Ac-Arg-Phe-Met-Trp-Met-Lys-NH2）用β(2)-色氨酸类似物取代 Trp 导致镇痛作用增强且持续时间延长。这些结果使我们假设阿片受体和 NOP 受体都参与了新合成化合物的镇痛作用。
