Systemically-Active Galanin Analogs

描述（由申请人提供）：癫痫是一种使人衰弱的神经系统疾病，影响全球约5000万至6000万人。不幸的是，只有70%的患者有效地治疗可用的抗惊厥药物。这项R21资助申请的目标是表征我们实验室发现的独特的基于加兰他敏的化合物治疗药物耐药性癫痫的能力。Galantine是一种抗惊厥神经肽，为开发新型抗癫痫药物提供了独特的机会，但这种肽表现出差的代谢稳定性，并且不能穿透血脑屏障。我们的结果表明，我们已经成功地设计了具有全身活性的抗惊厥药加兰他汀类似物，其在代谢和构象上更稳定，并且可以穿透血脑屏障，并且对两种加兰他汀受体亚型保持高亲和力。加兰他汀类似物的全身生物利用度的获得是几种化学修饰的明智组合的结果，其中与阳离子化偶联的特定唇氨基酸似乎是关键组分。在本授权申请中，我们提出测试一个假设，即通过优化关键的唇氨基酸取代基的长度，我们将改善甘丙肽类似物的全身活性，而不影响受体结合特性。将使用脂氨基酸的长度与几个物理化学和功能参数之间的相关性来剖析代谢稳定性、亲脂性和构象在改善甘丙肽类似物的全身生物利用度中的作用，从而提供脂氨基酸如何可以增加这些独特的抗惊厥肽的全身活性的重要机理性见解。 公共卫生相关性：该项目旨在促进对甘丙肽及其受体在癫痫中的作用的更深入了解。我们建议合成一系列独特的抗癫痫化合物，这些化合物可以进入负责癫痫发作活动启动和传播的大脑关键部位。这些化合物将用于研究癫痫发作的机制，并最终用于预防，减缓或阻止癫痫发展的新治疗策略。

DESCRIPTION (provided by applicant): Epilepsy is a debilitating neurological disorder that affects approximately 50-60 million people worldwide. Unfortunately, only 70% of patients are effectively treated with available anticonvulsant drugs. The goal of this R21 grant application is to characterize unique galantine-based compounds discovered in our laboratory for their ability to treat pharmaco-resistant epilepsy. Galantine is an anticonvulsant neuropeptide that provides a unique opportunity to develop novel antiepileptic drugs, but this peptide exhibits poor metabolic stability and does not penetrate the blood-brain-barrier. Our results suggest that we have successfully designed systemically-active anticonvulsant galantine analogs that are: metabolically and conformationally more stable, AND can penetrate the blood- brain-barrier, AND retain high affinity toward two galantine receptor subtypes. The gain of the systemic bioavailability of the galantine analogs was a result of a judicious combination of several chemical modifications, of which a specific lip amino acid coupled to cationization appeared to be critical components. In the present grant application, we propose to test a hypothesis that by optimizing the length of the critical lip amino acid substituent, we will improve systemic activity of the galanin analogs, without affecting receptor binding properties. Correlations between the length of the lipoamino acid and several physico-chemical and functional parameters will be used to dissect a role of metabolic stability, lipophilicity and conformation in improving systemic bioavailability of the galanin analogs, thus providing an important mechanistic insight into how the lipoamino acid may increase systemic activity of these unique anticonvulsant peptides. PUBLIC HEALTH RELEVANCE: This project aims to advance a greater understanding of the role of galanin and their receptors in epilepsy. We propose to synthesize a series of unique antiepileptic compounds that can access critical parts of the brain responsible for the initiation and propagation of seizure activity. Such compounds will be used to study the mechanisms of seizures in epilepsy and ultimately to a novel therapeutic strategy for preventing, slowing or halting the development of epilepsy.