Opioid Peptides--Molecular Mechanism Of Action

工作总结：总体研究包括对两个不同家族的阿片类化合物的研究，即高度特异性μ-选择性阿片肽的内源性内吗啡肽家族的衍生物和由通式R-Dmt-Tic-R '-R”组成的同等有效的δ-阿片受体拮抗剂肽家族，研究了影响这些化合物生物活性的几个相关因素。首先，就内吗啡肽而言，[Dmt-1] endomorphin-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，抑制体内吗啡抗伤害感受，并抑制乙醇诱导的海马神经元自发IPSC。Dmt-Tic药效团的修饰包括N-烷基化（R）、接头长度和组成（R '）以及化合物的C-末端组成（R”），其包括各种荧光部分。Dmt-Tic药效化合物表现出高δ-阿片受体亲和力（Ki小于0.1 nM），而高μ-阿片受体亲和力（Ki约或小于1 nM）取决于两个因素：不带电的C-末端或存在赖氨酸残基，大的疏水或芳香基团（Bid或Ph）。通过改变接头的长度（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也形成具有有效δ和μ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）。这些数据已提交专利保护。数据证实Dmt是所有活性的关键残基，并且分子的轻微修饰，无论是Dmt-Tic药效团还是内吗啡肽，都在生物活性谱中提供了显著变化。这些独特的分子具有应用于对抗各种人类疾病状态的潜力：μ-阿片样物质拮抗剂可用于治疗肥胖和酒精中毒，而δ-阿片样物质激动剂可缓解与哮喘相关的慢性问题。

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-1]endodomorphin-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. These data were submitted 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.