Opioid Peptides--Molecular Mechanism Of Action

阿片肽--作用分子机制

基本信息

批准号：
7593968
负责人：
LAWRENCE H LAZARUS
金额：
$ 29.75万
依托单位：
NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/7593968
关键词：
Ache Acute Addictive Behavior Affect Affinity Agonist Alcohol dependence Alcoholism Alcohols Alkylation Analgesics Anorexia Nervosa Appearance Asthma Back Binding Blood - brain barrier anatomy Brain Bulimia C-terminal Cells Characteristics Charge Chronic Computers Condition Data Dietary intake Disease Eating Disorders End Point Ethanol Exhibits Family Food Gambling Hand Hippocampus (Brain)Human Image Immune Intervention Invasive Lead Legal patent Length Ligands Lung Lung Neoplasms Malignant Neoplasms Medicine Minor Modification Molecular Mechanisms of Action Morphine N-terminal Narcotic Antagonists Narcotics Neurons Oat Cell Obesity Opioid Opioid Peptide Opioid Receptor Pain Pathogenesis Pathway interactions Peptides Perception Peripheral Pharmaceutical Preparations Physiological Positron-Emission Tomography Post-Traumatic Stress Disorders Predisposition Property Research Rewards Role playing therapy Smoking Staging Stress Structure Symptoms System Television Therapeutic Today Tracer Trauma Twin Multiple Birth Tyrosine Video Games Weight Gain Work addiction alcohol craving analog base clinically significant craving delta opioid receptor drug craving food craving glycyllysine human disease in vivo lung cancer screening mu opioid receptors neural circuit neurobehavioral obesity treatment pharmacophore pleasure psychologic receptor relating to nervous system response trait

项目摘要

Summary of Work: The overall studies encompassed research on two distinct family of opioid compounds, derivatives of the endogenous endomorphin family of highly specific mu-selective opioid peptides and the equallly potent delta-opioid receptor antagonist family of peptides, consisting of the general formula R-Dmt-Tic-R-R, investigated several pertinent factors on the bioactivity of these compounds. First, in terms of the endomorphins, N-monoallylation of Dmt-1endodomorphin-1 and -2 converted a mu agonist into a specific mu antagonist: they exhibited neutral antagonism, suppressed morphine antinociception in vivo, and inhibited the ethanol-induced spontaneous IPSC in hippocampal neurons. Modifications of the Dmt-Tic pharmacophore, included N-alkylation (R), linker length and composition (R), and the C-terminal composition of the compound (R), which included various fluorescent moieties. The Dmt-Tic pharmacophoric compounds exhibited high delta-opioid receptor affinities (Ki less than 0.1 nM), while high mu-opioid receptor affinities (Ki approximately or less than 1 nM) depended two factors: a non-charged C-terminus or the presence of a Lys residue, a large hydrophobic or aromatic group (Bid or Ph). The inherent delta antagonism was conversted to an agonist by altering the length of the linker (R = Gly, R = Bid) and reverted back to an antagonist substitution of Gly by Lys; however, Lys also formed a non-selective molecule with potent delta and mu antagonism. One fluorescent derivative have highly selectivity (greater than 4,000) for the delta-opioid receptor as a non-competitive or irreversible antagonist; data were submitted as an EIR for patent protection. The data verified that Dmt is the key residue for all activity and slight modification of the molecules, be the Dmt-Tic pharmacophore or endomorphins provides significant changes in the bioactivity spectrum. These unique molecules have the potential for application to combat various human disease states: mu-opioid antagonists could be applicable in treatment of obesity and alcoholism, while delta-opoid agonists might alleviate chronic problems associated with asthma. In addition, specific synthsized analogues containing Dmt-Tic and the tracer 18-F selectively bind to delta-opioid receptors as antagonists exisiting on oat cell carinoma cells in lungs as visualized by PET scans. The potential of these compounds lies in their ability to image lung tumors in vivo without invasive surgerical intervention and may be suitable for the early detection of lung cancer; a provision patent was filed.

工作总结：总体研究包括对两个不同家族的阿片化合物的研究，即高度特异性 mu 选择性阿片肽的内源性内吗啡肽家族的衍生物和同样有效的 δ-阿片受体拮抗剂肽家族，由通式 R 组成-Dmt-Tic-R-R，研究了这些化合物生物活性的几个相关因素。首先，就内吗啡而言，Dmt-1endodomorphin-1和-2的N-单烯丙基化将mu激动剂转化为特异性mu拮抗剂：它们表现出中性拮抗作用，抑制体内吗啡镇痛作用，并抑制乙醇诱导的自发IPSC海马神经元。 Dmt-Tic 药效团的修饰包括 N-烷基化 (R)、接头长度和组成 (R)，以及化合物 (R) 的 C 末端组成，其中包括各种荧光部分。 Dmt-Tic 药效团化合物表现出高 δ-阿片受体亲和力（Ki 小于 0.1 nM），而高 mu-阿片受体亲和力（Ki 大约或小于 1 nM）取决于两个因素：不带电荷的 C 端或存在赖氨酸残基、大的疏水基团或芳香基团（Bid 或 Ph）。通过改变连接子的长度（R = Gly，R = Bid）将固有的δ拮抗作用转化为激动剂，并恢复为由Lys取代Gly的拮抗剂；然而，Lys 也形成了具有强效 delta 和 mu 拮抗作用的非选择性分子。一种荧光衍生物作为非竞争性或不可逆拮抗剂对δ-阿片受体具有高度选择性（大于4,000）；数据作为 EIR 提交以进行专利保护。数据证实，Dmt 是所有活性的关键残基，分子的轻微修饰，无论是 Dmt-Tic 药效团还是内吗啡素，都可以使生物活性谱发生显着变化。这些独特的分子具有对抗各种人类疾病状态的潜力：μ阿片拮抗剂可用于治疗肥胖和酗酒，而δ阿片激动剂则可缓解与哮喘相关的慢性问题。此外，含有 Dmt-Tic 和示踪剂 18-F 的特定合成类似物选择性地与 δ-阿片受体结合，作为存在于肺部燕麦细胞癌细胞上的拮抗剂，如 PET 扫描所示。这些化合物的潜力在于它们能够在无需侵入性手术干预的情况下对体内肺部肿瘤进行成像，并且可能适用于肺癌的早期检测；已申请一项规定专利。