Pharmacology of Neuroendocrine Peptides

神经内分泌肽药理学

• 批准号: 8564667
• 负责人: JEAN E RIVIER
• 金额: $ 40.41万
• 依托单位: SALK INSTITUTE FOR BIOLOGICAL STUDIES
• 依托单位国家: 美国
• 财政年份: 1996
• 资助国家: 美国
• 起止时间: 1996-04-01 至 2015-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8564667
• 关键词: Affect; Agonist; Amino Acids; Antibodies; Antidepressive Agents; Binding; Binding Proteins; Biology; Blood - brain barrier anatomy; Calcitonin; Cardiovascular system; Chronic; Chronic stress; Clinical; Clinical Trials; Collaborations; Communities; Corticotropin-Releasing Hormone; Corticotropin-Releasing Hormone Receptors; Diabetes Mellitus; Discipline; Disease; Disease remission; Diuretics; Drug Industry; Drug Kinetics; Endocrine; Family; Feedback; GNAI2 gene; Generations; Glucagon; Goals; Health; Homeostasis; Hormones; Human; Immune; Instruction; Irritable Bowel Syndrome; Ligands; Mental Depression; Metabolism; Modeling; Molecular Conformation; Mus; N-terminal; NMR Spectroscopy; Neuraxis; Neurosecretory Systems; Pathology; Peptides; Peripheral; Pharmacologic Substance; Pharmacology; Phase; Physiological; Play; Processed Genes; Property; Psoriasis; Relapse; Research; Role; Secretin; Skin; Somatotropin-Releasing Hormone; Stimulus; Stress; Structure; Symptoms; System; Testing; X-Ray Crystallography; acute stress; analog; astressin; base; design; drug candidate; gastrointestinal; gastrointestinal system; glucagon-like peptide 1; in vitro Bioassay; in vivo; member; novel; peptide analog; peptide structure; pituitary adenylate cyclase activating polypeptide; programs; receptor; reproductive; response; success; tool; urocortin

Advances in the understanding of the mechanisms of action of corticotropin releasing factor (CRF)/urocortins (Ucn), the stress hormones, and possible clinical indications resulted from the availability of refined tools that include the two CRF receptors (CRFRl and CRFR2) and their subtypes, antibodies to the different native ligands, and a number of synthetic analogs including receptor-selective agonists and antagonists. CRF, urocortins and their two receptors are widely distributed and affect the cardiovascular, gastrointestinal, immune, skin, reproductive, central nervous systems and metabolism where they play an important role in maintaining homeostasis. Chronic over-stimulation of these systems leads to diseases such as depression. Irritable Bowel Syndrome, psoriasis and many others. There is mounting evidence that the administration of CRFs' antagonists may ultimately alleviate symptoms in, or even cure, most diseases with stress-induced relapses. To test this hypothesis, safe, long acting and receptor-selective analogs need to be identified. Whereas we have designed long acting non-selective CRF antagonists (astressins), antagonists that are CRFR2-selecfive (astressin2-B) and CRFR1-selective agonists (stressini), we propose to complete our panoply of drug candidates with the design of a peptide CRFRl antagonist and a long acting CRFR2 agonist. We may reach this goal with the long standing complementary contributions of other members of the Program Project (Project 1 for in vitro bioassays, Project 3 for the determination of the structure of the interaction between receptor and ligands and Project 4 and outside collaborators for in vivo studies). The unusual gene processing of Ucn 2 and Ucn 3 may be clarified with the availability of synthetic N-terminally extended fragments in collaboration with Project 1.

了解皮质激素释放因子（CRF）/尿素蛋白（UCN），应激激素以及可能的临床指示的进步，包括两种CRF受体（CRFRL和CRFR2）及其亚型，包括不同的本地ligands和Norders的抗体，以及包括两个CRF受体（CRFRL和CRFR2）的可用性所产生的临床指示，包括对手。 CRF，泌尿皮质素及其两个受体分布广泛，并影响心血管，胃肠道，免疫，皮肤，生殖，中枢神经系统和代谢，在维持体内平衡中起重要作用。这些系统的慢性过度刺激导致抑郁等疾病。肠易激综合症，牛皮癣和许多其他综合症。有越来越多的证据表明，CRF的拮抗剂的给药最终可能减轻大多数患有压力引起的复发的疾病，甚至可以治愈大多数疾病。为了检验这一假设，需要确定安全，长作用和受体选择性类似物。尽管我们设计了长期表演的非选择性的CRF拮抗剂（ASSRASTINS），CRFR2-固定的拮抗剂（assressin2-B）和CRFR1选择性激动剂（Pressini），但我们建议通过设计Apphite Crfrl Crfrl Anagogonist和Long Long Acting Crfr2 Agonists Agonists的设计来完成我们的候选药物候选者。我们可能会通过该计划项目的其他成员的长期互补贡献（用于体外生物测定的项目1，项目3，用于确定受体与配体之间的相互作用结构以及项目4和外部合作者的体内研究）的长期互补贡献。 UCN 2和UCN 3的异常基因处理可以通过与项目1合作的合成N末端扩展片段的可用性来阐明。