Systemically-Active Galanin Analogs

系统活性甘丙肽类似物

• 批准号: 7531411
• 负责人: GRZEGORZ BULAJ
• 金额: $ 19.75万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-08-01 至 2010-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7531411
• 关键词: Acids; Address; Affect; Affinity; Alzheimer' s Disease; Amino Acids; Animal Model; Animals; Anticonvulsants; Antiepileptic Agents; Antiepileptogenic; Applications Grants; Binding; Bioavailable; Biological Availability; Blood - brain barrier anatomy; Brain; Brain Part; Central Nervous System Diseases; Chemicals; Classification; Clinical; Communities; Coupled; Data; Development; Disease; Dose; Engineering; Epilepsy; Exhibits; Fire - disasters; Frequencies; Future; Galanin; Goals; Half-Life; Kindling (Neurology); Knowledge; Laboratories; Lead; Length; Lip structure; Mediating; Membrane; Mental Depression; Metabolic; Methods; Micelles; Modeling; Modification; Molecular Conformation; Molecular Weight; Motor Seizures; Neuromodulator; Neurons; Neuropeptides; Numbers; Octanols; Pain; Partition Coefficient; Patients; Penetration; Peptides; Performance; Plasma; Play; Process; Property; Public Health; Refractory; Resistance; Role; Seizures; Series; Somatostatin; Structure-Activity Relationship; Testing; Therapeutic; Water; analog; base; chemical property; cytotoxicity; design; galanin receptor; improved; indexing; insight; lipophilicity; mouse model; nervous system disorder; novel; novel therapeutics; painful neuropathy; peptide analog; prevent; receptor; receptor binding; research study; response; surfactant; therapeutic target; therapy resistant; tool

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.

描述（由申请人提供）：癫痫是一种令人衰弱的神经系统疾病，影响了全球约500-6亿人。不幸的是，只有70％的患者有效地接受了可用的抗惊厥药物治疗。此R21赠款应用程序的目的是表征我们实验室中发现的独特基于Galantine的化合物，以治疗耐药性癫痫的能力。 Galantine是一种抗惊厥药神经肽，为开发新型抗癫痫药提供了独特的机会，但是该肽表现出较差的代谢稳定性，并且不会穿透血脑屏障。我们的结果表明，我们已经成功地设计了系统活跃的抗惊厥药类似物，这些类似物是：在代谢上和构象上更稳定，可以穿透血液 - 脑障碍，并保留对两个Galantine受体亚型的高亲和力。 Galantine类似物的全身生物利用度的获取是几种化学修饰的明智组合的结果，其中特定的唇氨基酸与阳离子化似乎是关键的成分。在本授予的应用中，我们建议检验一个假设，即通过优化临界氨基酸取代基的长度，我们将改善Galanin类似物的全身活动，而不会影响受体结合特性。脂氨基酸的长度与几种物理化学和功能参数之间的相关性将用于剖析代谢稳定性，亲脂性和构象在改善甘烷蛋白类似物的全身生物利用度中的作用，从而提供了对这些独特的独特的独特的机制的重要机制，从而提供了重要的机制。 公共卫生相关性：该项目旨在提高对加拉宁及其受体在癫痫中的作用的更多了解。我们建议合成一系列独特的抗癫痫化合物，这些化合物可以访问负责发作和传播活性的大脑的关键部分。这种化合物将用于研究癫痫中癫痫发作的机制，并最终用于预防，放缓或停止癫痫发育的新型治疗策略。