RECEPTOR SPECIFIC ENKEPHALIN ANALOGUES

受体特异性脑啡肽类似物

• 批准号: 2263725
• 负责人: Victor J Hruby
• 金额: $ 18.56万
• 依托单位: UNIVERSITY OF ARIZONA
• 依托单位国家: 美国
• 财政年份: 1984
• 资助国家: 美国
• 起止时间: 1984-04-01 至 1994-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2263725
• 关键词: autoradiography; behavioral medicine; binding proteins; brain metabolism; chemical structure function; conformation; drug addiction antagonist; drug metabolism; drug quality /standard; enkephalins; guinea pigs; hamsters; high performance liquid chromatography; hormone receptor; hormone regulation /control mechanism; ion exchange chromatography; laboratory mouse; laboratory rabbit; laboratory rat; narcotic antagonists; neuropeptide receptor; neuropeptides; neuropharmacology; nuclear magnetic resonance spectroscopy; opiate alkaloid; peptide analog; peptide chemical synthesis; protein engineering; radiotracer; synthetic peptide

We propose to develop a series of cyclic and otherwise conformationally restricted peptide analogues which have high receptor selectivity, high agonist or antagonist potency, high stability in vivo, and prolonged activity for delta and mu opioid receptors. For this purpose, our program utilizes a multidisciplinary approach combining modern synthetic amino acid and peptide chemistry, conformational analysis, dynamics, and peptide drug design, with biochemical, biophysical, physiological, and behavior pharmacology. Our specific aims include: 1) design, synthesis and evaluation of novel enkephalin analogues with delta opioid receptor agonist activity and selectivity; 2) development of delta opioid receptor antagonists with high selectivity; 3) design, synthesis and evaluation of cycli, conformationally-constrained somatostatin-like peptides with little or no somatostatin activity, but with high potency and specificity for mu opioid receptors; 4) examination in detail of the conformational and dynamic properties of the most potent and selective analogues from 1, 2, and 3 to obtain insight into the rational design of more selective or potent analogues using modern graphics and computational methods; 5) to examine in detail the binding activities of these compounds at mu and delta opioid receptors (the most selective analogues with be radiolabeled and receptor localized in the brain by modern autoradiographic methods); 6) to obtain a comprehensive evaluation of the opioid agonist and antagonist in vitro and in vivo activities of the analogues we have prepared and compare these activities with standard drugs; and 7) to use the above results to design more specific and more potent analogues for the delta and mu receptor. The long term goals of this research are to develop an understanding of the physiological roles of the various opioid receptors, and to develop ligands for these receptors which can be used for the treatment of disease.

我们建议发展一系列旋回和其他构象

项目成果

Autoradiographic localization of delta opioid receptors in the rat brain using a highly selective bis-penicillamine cyclic enkephalin analog.

使用高选择性双青霉胺环状脑啡肽类似物对大鼠大脑中 δ 阿片受体进行放射自显影定位。

• DOI: 10.1016/0014-2999(85)90770-8
• 发表时间: 1985
• 期刊: European journal of pharmacology
• 影响因子: 5
• 作者: Gulya,K;Gehlert,DR;Wamsley,JK;Mosberg,HI;Hruby,VJ;Duckles,SP;Yamamura,HI
• 通讯作者: Yamamura,HI

Light microscopic autoradiographic localization of delta opioid receptors in the rat brain using a highly selective bis-penicillamine cyclic enkephalin analog.

使用高选择性双青霉胺环状脑啡肽类似物对大鼠大脑中 δ 阿片受体进行光显微放射自显影定位。

• 发表时间: 1986
• 期刊: The Journal of pharmacology and experimental therapeutics
• 作者: Gulya,K;Gehlert,DR;Wamsley,JK;Mosberg,H;Hruby,VJ;Yamamura,HI
• 通讯作者: Yamamura,HI

Opioid peptides: simultaneous delta agonism and mu antagonism in somatostatin analogues.

阿片肽：生长抑素类似物同时具有 δ 激动作用和 mu 拮抗作用。

• DOI: 10.1016/s0196-9781(96)00242-2
• 发表时间: 1997
• 期刊: Peptides
• 影响因子: 3
• 作者: Bonner,GG;Davis,P;Stropova,D;Ferguson,R;Yamamura,HI;Porreca,F;Hruby,VJ
• 通讯作者: Hruby,VJ

Structure-activity analysis of five constrained somatostatin like peptides with opioid antagonist properties.

五种具有阿片拮抗剂特性的受限生长抑素样肽的结构活性分析。

• 发表时间: 1987
• 期刊: Proceedings of the Western Pharmacology Society
• 作者: Wire,WS;Pelton,JT;Kazmierski,W;Hruby,VJ;Burks,TF;Shook,JE
• 通讯作者: Shook,JE

A high affinity, highly selective ligand for the delta opioid receptor: [3H]-[D-Pen2, pCl-Phe4, d-Pen5]enkephalin.

δ 阿片受体的高亲和力、高选择性配体：[3H]-[D-Pen2、pCl-Phe4、d-Pen5]脑啡肽。

• DOI: 10.1016/0024-3205(89)90154-9
• 发表时间: 1989
• 期刊: Life sciences
• 影响因子: 6.1
• 作者: Vaughn,LK;Knapp,RJ;Toth,G;Wan,YP;Hruby,VJ;Yamamura,HI
• 通讯作者: Yamamura,HI