Bonney Iwona Maszczynska, Foran Stacy E, Marchand James E, Lipkowski Andrzej W, Carr Daniel B
Department of Anesthesia, Tufts-New England Medical Center, 750 Washington Street, Boston, MA 02111, USA.
Eur J Pharmacol. 2004 Mar 19;488(1-3):91-9. doi: 10.1016/j.ejphar.2004.02.023.
The use of "multimodal" combination analgesic therapies or novel single molecules possessing multiple analgesic targets is becoming increasingly attractive. In previous experiments we showed that a substance P antagonist injected intrathecally potentiated the antinociceptive effects of potent opioid receptor agonist, biphalin. Based on examination of the biphalin structure-activity relationship, we designed and synthesized a novel chimeric peptide, termed AA501 (N'(Tyr-D-Ala-Gly-Phe), N"(Z-Trp) hydrazide, Z=benzyloxycarbonyl). AA501 consists of an opioid receptor agonist pharmacophore related to biphalin and a substance P receptor antagonist pharmacophore, both linked by a hydrazide bridge. The present study evaluates the ability of a novel chimeric peptide, AA501, to bind to opioid and substance P receptors and to produce antinociception in tail-flick and formalin tests, and in a neuropathic pain model when administered intrathecally to rats.
使用“多模式”联合镇痛疗法或具有多个镇痛靶点的新型单一分子正变得越来越有吸引力。在先前的实验中，我们表明鞘内注射P物质拮抗剂可增强强效阿片受体激动剂比法林的镇痛作用。基于对比法林结构-活性关系的研究，我们设计并合成了一种新型嵌合肽，称为AA501（N'(酪氨酸-D-丙氨酸-甘氨酸-苯丙氨酸)，N"(Z-色氨酸)酰肼，Z =苄氧羰基）。AA501由与比法林相关的阿片受体激动剂药效基团和P物质受体拮抗剂药效基团组成，两者通过酰肼桥连接。本研究评估了新型嵌合肽AA501与阿片受体和P物质受体结合的能力，以及在甩尾试验和福尔马林试验中，以及在对大鼠鞘内给药时在神经性疼痛模型中产生镇痛作用的能力。
