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.

促肾上腺皮质激素释放因子（CRF）和尿皮质素（Ucn）的肽类拮抗剂在了解不同应激刺激下的内分泌、免疫、心血管和胃肠道功能方面发挥了重要作用。非肽CRF拮抗剂是为治疗抑郁症而开发的。此外，由于CRF受体选择性激动剂和拮抗剂的可用性，两种不同的CRF受体（CRFR1和CRFR2）及其亚型的实际功能、分布和特异性现在得到了更好的了解。然而，多个CRF天然配体（CRF和CRF）之间的氨基酸序列存在显著差异