TRANSPORT OF OPIOID PEPTIDE ANALGESICS INTO THE BRAIN

该基金旨在开发代谢稳定、易于穿过血脑屏障、具有高镇痛功效且副作用最小的新型偶联阿片肽药物。Protein Delivery Inc.开发了一种新技术，允许多肽运输到中枢神经系统，并保护它们免受酶代谢的影响。这种两亲性寡聚物偶联技术已应用于内源性脑啡肽。初步实验表明，经静脉给药后，结合脑啡肽在大鼠热板实验中产生了强效、持久的镇痛作用。相比之下，未结合的脑啡肽没有镇痛活性，即使在高20倍剂量的测试中也是如此。体外研究表明，结合的脑啡肽在与脑匀浆孵育时非常稳定，孵育1小时后几乎没有降解，而未结合的脑啡肽在15分钟内完全降解。因此，独特的肽偶联技术对新型镇痛疗法的发展具有重要意义。我们建议研究在一系列镇痛试验中选择性作用于mu， delta和kappa阿片受体的其他共轭阿片肽。最终，我们打算进一步开发这种使能技术，以产生一种新的阿片肽镇痛剂，这种镇痛剂在受体选择性和治疗指标以及治疗神经性疼痛等疾病方面都具有优势。建议的商业应用：需要具有优越治疗指数的新型镇痛药来治疗慢性疼痛。考虑到美国有34- 5000万慢性疼痛患者，商业机会和临床需求是巨大的。结合肽技术促进了跨血脑屏障的运输，可以应用于许多神经活性肽。

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.