TRANSPORT OF OPIOID PEPTIDE ANALGESICS INTO THE BRAIN

这项拨款建议开发代谢稳定、容易跨越血脑屏障、具有高止痛效果和最小副作用的新型结合阿片肽药物。Protein Delivery Inc.开发了一种新技术，允许多肽进入中枢神经系统，并保护它们免受酶代谢的影响。这种两亲性低聚物偶联技术已应用于内源性脑啡肽。初步实验表明，静脉给药后，在大鼠热板试验中，结合脑啡肽产生了有效的、持久的镇痛作用。相比之下，未结合脑啡肽没有止痛活性，即使在测试剂量高出20倍时也是如此。体外研究表明，结合脑啡肽与脑匀浆孵育时非常稳定，孵育1小时后几乎没有降解，而非结合脑啡肽在15分钟内完全降解。因此，这种独特的多肽偶联技术对于开发新的止痛疗法具有重要的意义。我们建议研究其他结合阿片肽，这些阿片肽在一系列镇痛试验中选择性地作用于Mu、Delta和Kappa阿片受体。最终，我们打算进一步开发这一使能技术，以产生一类新的阿片肽止痛剂，这些止痛剂在受体选择性和治疗指数以及治疗神经病理性疼痛等方面具有优势。建议的商业应用：治疗慢性疼痛需要具有更高治疗指数的新型止痛药。鉴于美国有3400万至5000万慢性疼痛患者，商业机会和临床需求是巨大的。结合肽技术促进了血脑屏障的转运，并可应用于许多神经活性多肽。

This grant proposes to develop novel conjugated opioid peptide drugs that are metabolically stable, readily cross the blood-brain barrier and possess high analgesic efficacy with minimal side-effects. Protein Delivery Inc. has developed a novel technology that permits the transport of peptides into the CNS, and protects them from enzymatic metabolism. This amphophilic oligomer conjugation technology has been applied to endogenous enkephalin peptides. Preliminary experiments demonstrated that following intravenous administration, conjugated enkephalins produced potent, long-lasting analgesia in the rat hot-plate test. In contrast, unconjugated enkephalin had no analgesic activity, even when tested at a 20-fold higher dose. In vitro studies demonstrate that conjugated enkephalin is remarkably stable when incubated with brain homogenates, exhibiting little degradation after 1 hour incubation, while unconjugated enkephalin is completely degraded within 15 minutes. Thus, the unique peptide conjugation technology has powerful implications for the development of novel analgesic therapies. We propose to study other conjugated opioid peptides, which act selectively on mu, delta and kappa opioid receptors in a range of analgesic tests. Ultimately, we intend to further develop this enabling technology to generate a new class of opioid peptide analgesic agents that are superior in their receptor selectivity and therapeutic indices, as well as their ability to treat conditions such as neuropathic pain. PROPOSED COMMERCIAL APPLICATIONS: Novel analgesic agents with a superior therapeutic index are needed for the treatment of chronic pain. Given the 34-50 million chronic pain sufferers in the US, the commercial opportunities and clinical needs are great The conjugated peptide technology facilitates transport across the blood brain barrier, and could be applied to many neuroactive peptides.