Designing Novel Melanotropins for New Applications for the Melanocortin System

描述（由申报者提供）：黑素皮质素受体（melanocortin receptor, mcr）是g蛋白偶联受体（gpcr），调节和控制动物的许多关键生理过程，包括色素沉着、应激反应、摄食行为、能量平衡、性功能和行为、炎症反应、心血管功能、免疫反应、疼痛等。它们还与许多常见的退行性疾病有关，包括肾上腺功能障碍、肥胖、厌食症、色素紊乱、性功能障碍、长期神经性疼痛、炎症性疾病、心血管疾病等。然而，很少有化合物被开发出来，用于治疗这些疾病的药物是我们最常见和最难治疗的疾病。该基金致力于为褪黑素1（MCI）、黑素皮质素3 （MC3）、黑素皮质素4 （MC4）和黑素皮质素5 （MC5）受体开发更有效的、受体选择性的、特异性的和最有效的配体。这些新型配体具有生物稳定性和可在体内应用的特点，对研究促黑素配体的药理学、生理学和医学应用具有重要意义。我们将追求的具体目标包括：1)开发和使用新的蛋白质/肽拓扑结构和支架，结合新的约束氨基酸，设计和合成新的正构，变构和偏倚的促黑素肽和肽模拟物，增强黑素皮质素受体的稳定性，生物利用度，选择性和效力；2a)检测结合亲和力、环AMP的产生、有效性、Ca+2测定和ß-阻滞测定。将对hMC1R、hMC3R、hMC4R和hMC5R受体的新型配体进行研究，并特别关注偏配体的发展；2b)利用新的选择性配体，特别是那些具有偏倚活性的配体，与我们的合作者一起探索新的生理功能，从而产生新的药物。

DESCRIPTION (provided by applicant): The melanocortin receptors (MCRs) are G-Protein Coupled Receptors (GPCRs) that modulate and control many critical physiological processes in animals including pigmentation, response to stress, feeding behavior, energy balance, sexual function and behavior, inflammatory response, cardiovascular function, immune response, pain and others. They also are involved in many of our most common degenerative diseases including adrenal dysfunction, obesity, anorexia, pigmentary disorders, sexual dysfunction, prolonged and neuropathic pain, inflammatory disorders, cardiovascular disease and others. Yet there are few compounds that have been developed and are pharmaceuticals in use for treatment of these diseases which are our most common and difficult to treat diseases. This grant is dedicated to developing more potent, receptor selective, and specific and most efficacious ligands for the melancortin 1(MCI), melanocortin 3 (MC3), melanocortin 4 (MC4), and melanocortin 5 (MC5) receptors. These novel ligands, which are biological stable and available for in vivo applications, will be useful for studying the pharmacology, physiology and medical applications of melanotropin ligands. The specific aims we will pursue include: 1) development and use of novel protein/peptide topologies and scaffolds, in conjunction with novel constrained amino acids, to design and synthesize novel orthosteric, allosteric, and biased melanotropin peptides and peptide mimetics with enhanced stability, bioavailability, selectivity and potency for the melanocortin receptors; 2a) to examine binding affinities, cyclic AMP production, efficacies, Ca+2 assays and assays for ß-arrestin. The novel ligands for the hMC1R, hMC3R, hMC4R and hMC5R receptors will be examined with special attention to the development of biased ligands; and 2b) use of novel selective ligands, especially those with biased activity, to explore novel physiological functions that can lead to novel drugs with our collaborators.