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.

工作摘要：总体研究涵盖了对两种不同的阿片类化合物家族的研究，这是内源性内源性内源性家族的衍生物，具有高度特异性的MU选择性阿片类肽以及平稳性的肽肽家族的有效的三角洲 - 阿片类受体拮抗剂家族，由一般公式R-DMT-DMT-TIC-r-r-riio组成，这些因素是这些属于这些属于这些范围的per tore compolls of tore compound of tore compound oy tore compound conmoction in bontone conmound compoll conmound of tore boy compoiment oy tore bontiment。首先，就内胚剂而言，DMT-1端子形畸形1和-2的N-单声道化将MU激动剂转化为特定的MU拮抗剂：它们表现出中性拮抗作用，在体内抑制了吗啡抗吸引力，并抑制了乙醇诱导的乙醇诱导的IPSCC Inurons Inurons Inurons inuronsAronsAronsAnurons。 DMT-TIC药理的修饰，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药学化合物表现出高的三角洲受体亲和力（Ki小于0.1 nm），而高的Mu-Apioid受体亲和力（ki大约或小于1 nm）依赖两个因素：非电荷C-末端或溶质残留物的存在，或大量的Hydophobic或Aromatic（BID）（BID）。通过改变接头的长度（r = gly，r = bid），将固有的增量拮抗作用转化为激动剂，并恢复回到lys的拮抗剂替代。但是，LYS还形成了一个具有有效的三角洲和MU拮抗作用的非选择性分子。一种荧光衍生物具有高度选择性（大于4,000个），对于非竞争或不可逆的拮抗剂，三角洲阿片受体具有高度选择性；数据是作为专利保护的EIR提交的。数据证明了DMT是所有活性的关键残基，并且是分子的稍微修饰，是DMT-TIC药片或内啡肽可在生物活性谱中带来重大变化。这些独特的分子具有适用于各种人类疾病状态的潜力：MU-阿片类拮抗剂可能适用于肥胖和酒精中毒的治疗，而三角洲 - 蛋白酶激动剂可能会减轻与哮喘相关的慢性问题。此外，包含DMT-TIC和示踪剂18-F的特定合成类似物选择性地结合了Delta-Apoid受体，作为对PET扫描可视化的肺部颈椎细胞细胞上的拮抗剂。这些化合物的潜力在于它们在体内对肺部肿瘤进行成像而无需浸润性手术干预的能力，并且可能适合早期检测到肺癌。提交了一项条款专利。