Development of non-covalent chemical probes for mu, delta and kappa opioid receptors

尽管可待因在150多年前就已被分离出来，但人们对其与阿片受体的相互作用知之甚少。该项目的目的是加深对配体-阿片受体相互作用的基本了解。我们的工作将集中在系统地合成可待因二聚体作为阿片受体的非共价化学探针。分析新的非共价结合的二聚体与阿片受体的结合将有助于更好地理解配体-受体的相互作用，并由此产生新的结构-功能关系。新的科学知识的产生将加强我们对控制这一配体-受体功能的结构要求的理解，这一新的知识可能会为理解其他新的配体-受体对提供帮助。该项目的结果可能最终导致普渡制药开发一种新的安全药物。因此，加拿大人将从安全的非成瘾性止痛药的供应中受益匪浅。除了疼痛控制外，阿片受体还广泛参与各种生理和病理生理活动，包括调节细胞增殖、情绪反应、癫痫发作、免疫功能、摄食、肥胖、呼吸和心血管控制以及一些神经退行性疾病，包括阿尔茨海默病和帕金森病。因此，本研究将从药理学角度产生广泛的影响。

Despite the fact that codeine has been isolated over 150 years ago little is known about its interaction with opioid receptors. The aim of the project is to deepen a fundamental understanding of the ligand-opioid receptor interaction. Our efforts will focus on the systematic synthesis of codeine dimers as non-covalent chemical probes for opioid receptors. Analysis of novel non-covalently bound dimers to the opioid receptor will lead to a better understanding of ligand-receptor interaction and new structure-function relationships will emerge from this study. The generation of new scientific knowledge will enhance our understanding of the structural requirements that govern this ligand-receptor function, and this new knowledge may shed light in comprehending other novel ligand-receptor pairs. The results of this project may eventually lead to the development of a new class of safe drugs by Purdue Pharma. Therefore, Canadians will benefit immensely from the availability of safe non-addictive painkillers. In addition to pain management, opioid receptors are widely involved in various physiological and pathophysiological activities, including the regulation of cell proliferation, emotional response, epileptic seizures, immune function, feeding, obesity, respiratory and cardiovascular control as well as some neurodegenerative disorders including Alzheimer's and Parkinson's diseases. Therefore, this study will have a broad impact from pharmacological point of view.