The design of bifunctional compounds is a promising approach toward the development of strong analgesics with reduced side effects. We here report the optimization of the previously published lead peptide KGFF09, which contains opioid receptor agonist and neuropeptide FF receptor antagonist pharmacophores and is shown to induce potent antinociception and reduced side effects. We evaluated the novel hybrid peptides for their in vitro activity at MOP, NPFFR1, and NPFFR2 and selected four of them (DP08/14/32/50) for assessment of their acute antinociceptive activity in mice. We further selected DP32 and DP50 and observed that their antinociceptive activity is mostly peripherally mediated; they produced no respiratory depression, no hyperalgesia, significantly less tolerance, and strongly attenuated withdrawal syndrome, as compared to morphine and the recently FDA-approved TRV130. Overall, these data suggest that MOP agonist/NPFF receptor antagonist hybrids might represent an interesting strategy to develop novel analgesics with reduced side effects.

中文翻译：

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多靶点μ阿片受体激动剂─神经肽FF受体拮抗剂可诱导有效的镇痛作用并减少不良副作用

双功能化合物的设计是开发具有减少副作用的强效镇痛药的一种有前途的方法。我们在这里报告了先前发表的先导肽KGFF09的优化，其中含有阿片受体激动剂和神经肽 FF 受体拮抗剂药效团，并被证明可以诱导有效的镇痛作用并减少副作用。我们评估了新型混合肽对 MOP、NPFFR1 和 NPFFR2 的体外活性，并选择其中四种 ( DP08/14/32/50 ) 来评估其在小鼠中的急性镇痛活性。我们进一步选择了DP32和DP50并观察到它们的抗伤害活性主要是外周介导的；与吗啡和 FDA 最近批准的 TRV130 相比，它们不会产生呼吸抑制、痛觉过敏、耐受性显着降低以及戒断综合征的强烈减弱。总体而言，这些数据表明 MOP 激动剂/NPFF 受体拮抗剂混合物可能代表了开发副作用减少的新型镇痛药的有趣策略。