Opioid Peptides--Molecular Mechanism Of Action

阿片肽--作用分子机制

基本信息

批准号：
7734501
负责人：
LAWRENCE H LAZARUS
金额：
$ 27.49万
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/7734501
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 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 Label Lead Legal patent Length Ligands Lung Lung Neoplasms Malignant Neoplasms Medicine Membrane Minor Modification Molecular Mechanisms of Action Morphine N-terminal Narcotic Antagonists Narcotics Neurons 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 Role playing therapy Smoking Staging Stress Structure Surface Symptoms System Television Therapeutic Today Trauma Twin Multiple Birth Tyrosine Video Games Weight Gain Withdrawal Symptom addiction alcohol craving 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

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-R1-R2, investigated several pertinent factors on the bioactivity of these compounds. First, the endomorphins, N-allylDmt-1endodomorphin-1 and -2 became specific mu antagonists: exhibited neutral antagonism, suppressed morphine antinociception in vivo, eliminated morphine withdrawal symptoms completely, 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 (R1 = Gly, R2 = 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 had 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. Similarly an 18-F-labeled molecule only bound to systemic delta receptors, indicative of a potential role to reveal lung tumorlets non-invasively by PET scans, since these cancers express delta receptors in their surface membranes. 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. 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.

总体研究涵盖了对两种不同的阿片类化合物家族的研究，这是高度特异性的MU选择性阿片类肽的内源性内源性家族的衍生物，以及肽的平均有效的delta-Apioet受体拮抗剂家族，由一般的公式R-DMT-R-DMT-R12组成，这些肽由一般性的多数因子组成，这些因素是多数的。首先，内啡肽n- allyldMT-1端代方法和-2成为特定的MU拮抗剂：表现出中性拮抗作用，体内抑制吗啡抗伤害感受，完全消除了吗啡戒断症状，并抑制了乙醇诱导的乙醇诱导的IPSC。 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（r1 = gly，r2 = bid），将固有的三角拮抗作用转化为激动剂，并恢复为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）作为非竞争性或不可逆的拮抗剂的荧光衍生物。数据是作为专利保护的EIR提交的。同样，一个18-F标记的分子仅与全身三角洲受体结合，这表明通过PET扫描揭示肺肿瘤的潜在作用，因为这些癌症在其表面膜上表达了三角洲受体。这些化合物的潜力在于它们在体内对肺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。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。

项目成果

期刊论文数量（41）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Crystal structures of dipeptides containing the Dmt-Tic pharmacophore.

含有 Dmt-Tic 药效团的二肽的晶体结构。

DOI：
10.1021/jm020330p
发表时间：
2002
期刊：
Journal of medicinal chemistry
影响因子：
7.3
作者：
Bryant,SharonD;George,Clifford;Flippen-Anderson,JudithL;Deschamps,JeffreyR;Salvadori,Severo;Balboni,Gianfranco;Guerrini,Remo;Lazarus,LawrenceH
通讯作者：
Lazarus,LawrenceH

Enantioselective synthesis of a phenylalanine library containing alkyl groups on the aromatic moiety: confirmation of stereostructure by x-ray analysis.

芳香族部分含有烷基的苯丙氨酸文库的对映选择性合成：通过 X 射线分析确认立体结构。

DOI：
10.1248/cpb.54.873
发表时间：
2006
期刊：
Chemical & pharmaceutical bulletin
影响因子：
1.7
作者：
Li,Tingyou;Tsuda,Yuko;Minoura,Katsuhiko;In,Yasuko;Ishida,Toshimasa;Lazarus,LawrenceH;Okada,Yoshio
通讯作者：
Okada,Yoshio

Synthesis of opioidmimetics, 3-[H-Dmt-NH(CH(2))(m)]-6-[H-Dmt-NH(CH(2))(n)]-2(1H)-pyrazinones, and studies on structure-activity relationships.

阿片模拟物、3-[H-Dmt-NH(CH(2))(m)]-6-[H-Dmt-NH(CH(2))(n)]-2(1H)-吡嗪酮的合成，和

DOI：
10.2174/157340607782360272
发表时间：
2007
期刊：
Medicinal chemistry (Shariqah (United Arab Emirates))
影响因子：
0
作者：
Shiotani,Kimitaka;Miyazaki,Anna;Li,Tingyou;Tsuda,Yuko;Yokoi,Toshio;Ambo,Akihiro;Sasaki,Yusuke;Bryant,SharonD;Jinsmaa,Yunden;Lazarus,LawrenceH;Okada,Yoshio
通讯作者：
Okada,Yoshio

Inhibition of the development of morphine tolerance by a potent dual mu-delta-opioid antagonist, H-Dmt-Tic-Lys-NH-CH2-Ph.

DOI：
10.1016/j.pbb.2008.05.008
发表时间：
2008-10
期刊：
PHARMACOLOGY BIOCHEMISTRY AND BEHAVIOR
影响因子：
3.6
作者：
Jinsmaa, Yunden;Marczak, Ewa D.;Balboni, Gianfranco;Salvadori, Severo;Lazarus, Lawrence H.
通讯作者：
Lazarus, Lawrence H.

Selective delta-opioid receptor antagonist N,N(CH3)2-Dmt-Tic-OH does not reduce ethanol intake in alcohol-preferring AA rats.

选择性 δ-阿片受体拮抗剂 N,N(CH3)2-Dmt-Tic-OH 不会减少偏好酒精的 AA 大鼠的乙醇摄入量。