Pharmacology of neuroendocrine peptides

神经内分泌肽的药理学

• 批准号: 7429659
• 负责人: JEAN E RIVIER
• 金额: $ 38.05万
• 依托单位: SALK INSTITUTE FOR BIOLOGICAL STUDIES
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-06-01 至 2010-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7429659
• 关键词: Affect; Affinity; Agonist; Amino Acid Sequence; Amino Acids; Antibodies; Binding; Biological; Biological Assay; CRF receptor type 2; Calcitonin; Cardiovascular system; Chemicals; Class; Collaborations; Computer Simulation; Consensus; Corticotropin-Releasing Hormone; Corticotropin-Releasing Hormone Receptors; Dipeptides; Diuretics; Drug Kinetics; End Point; Endocrine; Etiology; Extracellular Domain; G Protein-Coupled Receptor Genes; Gastric Inhibitory Polypeptide; Glucagon; Hormones; Immune; Investigation; Laboratories; Lead; Letters; Ligand Binding; Ligands; Ligation; Mammals; Mental Depression; Modeling; Molecular Conformation; Mono-S; Mutate; Neurosecretory Systems; Parathyroid Hormones; Peptide Synthesis; Peptides; Peripheral; Pharmacologic Substance; Pharmacology; Physiological; Protein Fragment; Purpose; Reagent; Reporting; Research; Research Personnel; Role; Secretin; Side; Somatotropin-Releasing Hormone; Specificity; Stimulus; Stress; Structure; Structure-Activity Relationship; Tracer; aminoproline; analog; astressin B; base; design; gastrointestinal function; gastrointestinal system; human PTH protein; insight; novel; peptide analog; peptide structure; pharmacophore; pituitary adenylate cyclase activating polypeptide; programs; receptor; response; tool; urocortin

Peptidic antagonists of corticotropin releasing factor (CRF) and the urocortins (Ucn) have been critical in the understanding of endocrine, immune, cardiovascular and gastrointestinal functions in response to different stress stimuli. Nonpeptide CRF antagonists are developed for the treatment of depression. Further, the actual function, distribution and specificity of the two different CRF receptors (CRFR1 and CRFR2) and their subtypes are now better understood due to the availability of CRF-receptor-selective agonists and antagonists. However, significant amino acid sequence differences between the multiple CRF native ligands (CRF and Ucn 1, 2 and 3 in mammals) and the wide distribution of CRFR1 and CRFR2 with their concomitant modulation of multiple functions remain to be integrated and understood. There are two complementary end points to this Project: a) structural and b) pharmacological/biological. Both end points depend heavily on the synthesis of peptides (SPPS) and proteins (fragment chemical ligation). a) We propose to design and synthesize CRF/Ucn analogs and extra cellular domains 1 (ECD1s) of class B1 GPCR for functional and structural investigations using NMR in collaboration with Dr. Riek's project. Preliminary results have yielded a model of the interaction between the ECD1 of CRFR2 and the CRF antagonist, astressin B. Additional studies are mandatory to identify the actual contact points between ligands and the respective ECDs1 responsible for the initial steps of recognition and binding. This will be achieved with binding assays of mutated ECD1s and complementarily derivatized analogs of selected ligands. From these studies, we will derive consensus bioactive/binding conformations of the CRFR1 -selective and CRFR2-selective ligands and the pharmacophores of the respective receptors, b) We will use these pharmacophores in models for the rational design of novel peptide and nonpeptide CRFR1 and CRFR2 ligands. In particular, we propose to pursue the design of peptide CRFR1-selective antagonists using several approaches distinct from that used for the characterization of stressing a potent and CRFR1-selective agonist and astressin2-B, a potent and long acting CRFR2-selective antagonist. We will use these selective and potent reagents to identify through collaborations within this Program Project, and with outside investigators, the etiology of pathophysiological states for possible treatment.

皮质激素释放因子（CRF）和泌尿皮质蛋白（UCN）的肽拮抗剂对于理解内分泌，免疫，心血管和胃肠道功能至关重要。非肽CRF拮抗剂是为治疗抑郁症的。此外，由于CRF受体选择性激动剂和拮抗剂的可用性，现在更好地理解了两个不同CRF受体（CRFR1和CRFR2）及其亚型的实际功能，分布和特异性。但是，多个CRF天然配体之间的显着氨基酸序列差异（CRF和 哺乳动物中的UCN 1、2和3）以及CRFR1和CRFR2的广泛分布及其对多个功能的调制尚待集成和理解。该项目有两个互补的终点：a）结构和b）药理学/生物学。这两个端点都在很大程度上取决于肽（spps）和蛋白质（碎片化学连接）的合成。 a）我们建议使用NMR与Riek博士的项目合作设计和合成B1 GPCR的CRF/UCN类似物和额外的蜂窝域1（ECD1）1（ECD1），用于功能和结构研究。初步结果已经产生了CRFR2的ECD1与CRF拮抗剂，ASSTRESTIN B之间相互作用的模型。其他研究是 必须确定配体与各个ECDS1之间的实际接触点，负责识别和约束力的初始步骤。这将通过突变的ECD1的结合测定和选定配体的互补类似物来实现。从这些研究中，我们将得出CRFR1选择性和CRFR2选择配体的生物活性/结合构象以及相应受体的药物归根量，b）我们将在模型中使用这些药物算术来对新型肽和非肽CRFR1和CRFR1和CRFR2 Ligands进行合理设计。特别是，我们建议使用与该方法不同的方法来追求肽CRFR1选择性拮抗剂的设计 表征有效和CRFR1选择性激动剂和Asstressin2-B的表征，这是一种有效且作用很长的CRFR2选择性拮抗剂。我们将使用这些选择性和有效的试剂来通过该计划项目中的合作以及外部研究人员（病理生理状态的病因）来识别，以进行治疗。