Opioid Peptides--Molecular Mechanism Of Action

阿片肽--作用分子机制

基本信息

批准号：
7968133
负责人：
LAWRENCE H LAZARUS
金额：
$ 27.58万
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/7968133
关键词：
Ache Acute Addictive Behavior Affect Affinity Agonist Alcohol dependence Alcoholism Alcohols Analgesics Anorexia Nervosa Appearance Blood - brain barrier anatomy Brain Bulimia Characteristics Charge Chronic Computers Data Deposition Dietary intake Disease Eating Disorders Ethanol Exhibits FDA approved Family Food GABA-A Receptor Gambling Glucose Glutamates Hand Hippocampus (Brain)Hormones Human Immune Lead Leptin Ligands Malignant Neoplasms Medicine Minerals Minor Molecular Mechanisms of Action Morphinans Morphine Mus N-terminal Narcotic Antagonists Narcotics Neurons Obesity Opioid Opioid Peptide Opioid Receptor Oral Administration Osteoporosis Pain Pathogenesis Pathway interactions Peptides Perception Peripheral Pharmaceutical Preparations Physiological Play Post-Traumatic Stress Disorders Predisposition Property Research Rewards Role Serum Signal Transduction Smoking Staging Stress Structure Symptoms System Television Trauma Twin Multiple Birth Tyrosine Video Games Weight Gain Withdrawal Symptom addiction alcohol craving analog base bone clinically significant combat craving delta opioid receptor drug craving food craving human disease in vivo meetings mouse model mu opioid receptors neural circuit neurobehavioral neurotransmission pharmacophore pleasure psychologic relating to nervous system response trait

项目摘要

The overall study encompassed research on two distinct families of opioids: (1) N-allyl-Dmt-derivatives of the endogenous endomorphins, originally isolated from mammalian brain, constitute a potent and highly specific mu-selective opioid tetrapeptide agonists; and (2) the effective dual delta-/mu-opioid receptor antagonist peptide, H-Dmt-Tic-Lys-NH-CH2-Ph (MZ-2). First, the N-allyl-Dmtendodomorphin-1 and -2 analogs exhibited neutral antagonism, suppressed morphine antinociception in vivo, eliminated morphine withdrawal symptoms, and importantly inhibited the ethanol-induced spontaneous IPSC in hippocampal neurons governed by the glutamate neurotransmission system involving GABA-A receptors. The observed effect of these mu-antagonists was two orders of magnitude greater than a FDA approved drug, a derivative of the morphinans, to combat alcoholism. The dual acting Dmt-Tic pharmacophore compound exhibited high delta-opioid receptor affinity (Ki < 1 nM), while that for the mu-opioid receptor was very good (Ki approximately 4 nM); however, that activity depended on two structural factors: a non-charged C-terminus containing a hydrophobic group and the presence of a Lys residue, both of which are required for recognition by the mu-opioid receptor. Oral administration of MZ-2 exhibited potential human application in its ability in a mouse model of obesity (ob/ob mice) to reduce body weight gain, increase nocturnal activity in both obese and lean mice, enhance bone mineral deposition and produce positive effects on serum hormones and glucose levels. The data verify that these molecules could regulate or ameliorate alcoholism, obesity and osteoporosis. These unique molecules have therefore the potential for application to combat various human disease states which involve the neuronal reward mechanism in the brain: mu-opioid antagonists could be applicable in treatment of numerous disease states.

总体研究涵盖了对阿片类药物的两个不同家族的研究：（1）内源性内源代肽的N-酰基-DMT衍生物，最初是从哺乳动物大脑中分离出来的，构成了有效且高度特定的MU型阿片类四肽激动剂；（2）有效的双重delta-/mu阿片受体拮抗剂肽，H-DMT-TIC-LYS-NH-CH2-PH（MZ-2）。首先，N-酰基-DMTENDODOMORPHIN-1和-2类似物表现出中性拮抗作用，体内抑制了吗啡抗伤害感受，消除了吗啡戒断症状，并且重要的是抑制乙醇诱导的自发性IPSC，该神经神经素在受受度神经系统的受体中受到抑制。这些MU抗逆邦剂的观察到的效果是两个数量级，比FDA认可的药物（一种形态的衍生物）大于对抗酒精中毒。双重作用DMT-TIC药物团化合物表现出高藻类受体亲和力（Ki <1 nm），而对于Mu-Apoile受体的功能非常好（Ki大约4 nm）；然而，该活性取决于两个结构因素：一个非电荷的C末端，其中包含疏水基团和LYS残基的存在，这两者都是由MU-Apecioid受体识别所必需的。口服MZ-2在肥胖（OB/OB小鼠的小鼠模型（降低体重增加，增加肥胖小鼠）的夜间活性，增强骨骼矿物质沉积并对血清激素和葡萄糖水平产生积极影响的小鼠模型中，其能力表现出潜在的人类应用。数据证明这些分子可以调节或改善酒精中毒，肥胖和骨质疏松症。因此，这些独特的分子具有对抗各种人类疾病状态的潜力，涉及大脑中神经元的奖励机制：MU-阿片类拮抗剂可能适用于众多疾病状态的治疗。