<br>一种新型亮氨酸脑啡肽前药具有止痛和抗抑郁作用,Molecular Pharmaceutics

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一种新型亮氨酸脑啡肽前药具有止痛和抗抑郁作用
Molecular Pharmaceutics ( IF 4.5 ) Pub Date : 2024-01-20 , DOI: 10.1021/acs.molpharmaceut.3c00807
Lukas Hohenwarter ₁ , Ernest Puil ₂ , Elham Rouhollahi ₁ , Lennart Bohrmann ₁ , Shawna Lu ₁ , Katayoun Saatchi ₁ , Urs O Häfeli ₁ , Alasdair Barr ₂ , Roland Böttger ₁ , K K DurgaRao Viswanadham ₁ , Shyh-Dar Li ₁

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持续性疼痛是一个严重的医疗保健问题，治疗选择有限。慢性疼痛和抑郁症共病的高发生率显着降低了生活质量并使这两种疾病的治疗变得复杂。抗抑郁药对疼痛和抑郁症的治疗效果不如单独治疗抑郁症，而且会引起严重的副作用。阿片类药物是高效的镇痛药，但快速发展的耐受性、依赖性和使人衰弱的副作用限制了其功效和安全使用。亮氨酸脑啡肽 (Leu-ENK) 是一种内源性 δ 阿片受体激动剂，可控制疼痛和情绪，并产生有效的镇痛作用，与传统阿片类药物相比，可减少不良反应。然而，高蛋白水解不稳定性使得 Leu-ENK 在全身给药后无效，并限制了其临床用途。 KK-103 是一种 Leu-ENK 前药，旨在通过显着提高小鼠血浆稳定性来克服 Leu-ENK 的这些局限性。我们发现，与 Leu-ENK 相比，KK-103 的全身吸附和血浆暴露快速且显着增加。我们还观察到全身给药后大脑对放射性标记的 KK-103 的摄取，表明 KK-103 的中枢作用。然后，我们在斜坡热板和福尔马林测试中确定了 KK-103 的长期抗伤害功效。在这两种模型中，KK-103 产生的剂量与最大镇痛效果关系相当。 KK-103 的镇痛作用主要是由于 KK-103 在体内可能转化为 Leu-ENK 后激活 δ 阿片受体。最后，KK-103 产生了与抗抑郁药地昔帕明相当的抗抑郁样活性，但胃肠道抑制最小，并且没有镇静作用。

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A Novel Leu-Enkephalin Prodrug Produces Pain-Relieving and Antidepressant Effects

Persistent pain is a significant healthcare problem with limited treatment options. The high incidence of comorbid chronic pain and depression significantly reduces life quality and complicates the treatment of both conditions. Antidepressants are less effective for pain and depression than for depression alone and they induce severe side effects. Opioids are highly efficacious analgesics, but rapid development of tolerance, dependence, and debilitating side effects limit their efficacy and safe use. Leucine-enkephalin (Leu-ENK), the endogenous delta opioid receptor agonist, controls pain and mood and produces potent analgesia with reduced adverse effects compared to conventional opioids. High proteolytic instability, however, makes Leu-ENK ineffective after systemic administration and limits its clinical usefulness. KK-103, a Leu-ENK prodrug, was developed to overcome these limitations of Leu-ENK via markedly increased plasma stability in mice. We showed rapid and substantially increased systemic adsorption and blood plasma exposure of KK-103 compared to Leu-ENK. We also observed brain uptake of radiolabeled KK-103 after systemic administration, indicating a central effect of KK-103. We then established KK-103’s prolonged antinociceptive efficacy in the ramped hot plate and formalin test. In both models, KK-103 produced a comparable dose to the maximum antinociceptive-effect relationship. The pain-alleviating effect of KK-103 primarily resulted from activating the delta opioid receptor after the likely conversion of KK-103 to Leu-ENK in vivo. Finally, KK-103 produced an antidepressant-like activity comparable to the antidepressant desipramine, but with minimal gastrointestinal inhibition and no incidence of sedation.

更新日期：2024-01-20

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