Designing Novel Melanotropins for New Applications for the Melanocortin System

描述（由申请人提供）：黑皮质素受体（MCR）是G蛋白偶联受体（GPCR），可调节和控制动物体内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。它们还涉及许多我们最常见的退行性疾病，包括肾上腺功能障碍、肥胖、厌食、色素性疾病、性功能障碍、长期和神经性疼痛、炎性疾病、心血管疾病等。然而，很少有化合物已经被开发出来，并且是用于治疗这些疾病的药物，这些疾病是我们最常见和最难治疗的疾病。该基金致力于为黑皮质素1（MCI），黑皮质素3（MC 3），黑皮质素4（MC 4）和黑皮质素5（MC 5）受体开发更有效，受体选择性，特异性和最有效的配体。这些新的配体，这是生物稳定的，可用于在体内应用，将是有用的研究促黑激素配体的药理学，生理学和医学应用。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、变构和偏置促黑素肽和肽模拟物，其具有增强的稳定性、生物利用度、选择性和对黑皮质素受体的效力; 2a）检查结合亲和力、环AMP产生、效力、Ca+2测定和β-抑制蛋白测定。hMC 1 R，hMC 3R，hMC 4 R和hMC 5 R受体的新型配体将被检查，特别注意偏向配体的开发;和2b）使用新型选择性配体，特别是具有偏向活性的配体，以探索新的生理功能，可以与我们的合作者一起开发新的药物。

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.