Supplement for "Designing Novel Melanotropins for New Applications for the Melanocortin System"

描述(申请人提供)：黑素皮质素受体(MCR)是G蛋白偶联受体(GPCRs)，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。它们还与我们许多最常见的退行性疾病有关，包括肾上腺功能障碍、肥胖、厌食、色素障碍、性功能障碍、长期和神经性疼痛、炎症性疾病、心血管疾病等。然而，很少有化合物被开发出来并用于治疗这些疾病，这些疾病是我们最常见和最难治疗的疾病。这笔赠款致力于开发更有效、更具受体选择性、更特异和最有效的黑素皮质素1(MCI)、黑素皮质素3(MC3)、黑素皮质素4(MC4)和黑素皮质素5(MC5)受体的配体。这些新的配体具有生物稳定性，可用于体内应用，将有助于研究促黑素配体的药理、生理学和医学应用。我们将追求的具体目标包括：1)开发和使用新型蛋白质/多肽拓扑结构和支架，结合新型约束氨基酸，设计和合成具有增强的稳定性、生物利用度、选择性和有效性的新型邻位、变构和偏向促黑激素多肽和多肽模拟物；2a)检测�-arrestin的结合亲和力、环磷酸腺苷产量、有效性、Ca+2检测和检测方法。我们将考察hMC1R、hMC3R、hMC4R和hMC5R受体的新配体，特别关注偏向配基的发展；以及2b)使用新的选择性配基，特别是那些具有偏向活性的配基，以探索新的生理功能，从而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 �- 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.