Chemical biology of Peptide Regulation of Opioid Receptor Function

疼痛是每个人在他或她生命中的某个时刻都会意识到的一种感觉。不同的疼痛原因导致通过施用从阿司匹林到吗啡的药物作为当前的护理标准进行治疗。吗啡靶向阿片受体作为其“靶向”作用机制。不幸的是，长期治疗疼痛， 吗啡引起许多副作用，例如成瘾、耐受性、恶心、镇静、呼吸抑制、便秘等。因此，了解疼痛感知的不同机制，发现新的分子靶点以治疗疼痛，同时使不良副作用最小化，以及发现和开发新的治疗药物， 减轻疼痛的药物是全世界科学界不断努力的结果。本研究项目的目标是表征未探索的人类阿片受体N-末端结构域肽作为一种新的化学型用于治疗疼痛，以及它们如何调节阿片受体药理学。预期结果的影响 在药物化学和疼痛研究领域的研究，可以推进现有的阿片肽类药物的治疗，GPCR为基础的治疗配体设计策略的范例，以及提供新的工具，以探索疼痛管理的分子机制。

Pain is a sensation realized by every individual at some point in his or her lives. Different causes of pain result in treatment by administration of drugs ranging from aspirin to morphine as the current standard of care. Morphine targets the opioid receptors as its “on-target” mechanism of action. Unfortunately, prolonged treatment of pain with morphine causes many adverse effects such as addiction, tolerance, nausea, sedation, respiratory depression, constipation, and others. Thus, understanding the different mechanisms for pain perception, discovery of new molecular targets to treat pain with minimal undesired side effects, and the discovery and development of new therapeutic agents for the alleviation of pain is an on going effort by the scientific community world- wide. The goal of this research project is to characterize the unexplored human opioid receptor N-terminal domain peptides as a new chemotype for the treatment of pain and how they modulate opioid receptor pharmacology. The impact of the anticipated results on the medicinal chemistry and pain research fields could advance the existing paradigms for ligand design strategies for opioid peptide based therapeutics, GPCR based therapeutics, as well as provide novel tools to probe the molecular mechanisms of pain management.