DEVELOPMENT OF RECEPTOR-SPECIFIC OPIOID PEPTIDE ANALOGS

受体特异性阿片肽类似物的开发

• 批准号: 7665367
• 负责人: PETER W SCHILLER
• 金额: $ 17.56万
• 依托单位: CLINICAL RESEARCH INSTITUTE OF MONTREAL
• 依托单位国家: 美国
• 财政年份: 1987
• 资助国家: 美国
• 起止时间: 1987-06-01 至 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7665367
• 关键词: Agonist; Amino Acids; Analgesics; Binding; Bioavailable; Biological Assay; Carbon; Cavia; Charge; Chemistry; Cocaine; Cocaine Abuse; Ctenomyces; D-Phe-Pro; Dependence; Development; Discrimination; Drug abuse; Dynorphin A; Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; Enkephalins; GTP gamma S; Goals; Hydrogen Bonding; Hydroxyl Radical; In Vitro; Isomerism; Link; Modification; Molecular Conformation; Molecular Models; Mus; N-terminal; Narcotic Antagonists; Opioid; Opioid Peptide; Opioid Receptor; Opioid Receptor Binding; Organic Chemistry; Organic Synthesis; Pain; Parents; Peptide Synthesis; Peptides; Physical Dependence; Positioning Attribute; Property; Propionic Acids; Research; Research Personnel; Self Administration; Series; Structure; Testing; Therapeutic; Therapeutic Agents; Tyrosine; Vas deferens structure; Work; amino group; analog; base; cysteinylglycine; deltorphin; design; drug candidate; expectation; fungus; glycylphenylalanine; hydroxyl group; ileum; improved; in vivo; interdisciplinary approach; kappa opioid receptors; lysylphenylalanine; methyl group; molecular modeling; mu opioid receptors; novel; peptide analog; peptidomimetics; phenylalanylarginine; programs; receptor; rimorphin; tool; tyrosine analog; tyrosyl-1,2,3,4-tetrahydro-3-isoquinolinecarbonyl-phenylalanyl-phenylalanine; tyrosyl-arginyl-phenylalanyl-lysinamide

DESCRIPTION (provided by applicant): We propose to synthesize potent, stable and bioavailable opioid peptide analogues designed to be i) antagonists or inverse agonists with high selectivity for mu-, delta- or Kappa-opioid receptors and their subtypes as pharmacological tools and ii) opioid compounds with mixed agonist/antagonist profiles for possible therapeutic applications. To reach these goals, we use an interdisciplinary approach incorporating organic synthesis, peptide chemistry, extensive pharmacological characterization and conformational studies. Specific Aim 1 is based on our recent discovery that substitution of 3-(2,6-dimethyl-4-hydroxyphenyl)propanoic acid (Dhp) for the N-terminal tyrosine residue in opioid peptides produces antagonists at mu-, delta- or Kappa-receptors. We will synthesize Dhp analogues for Tyr1 replacement in opioid peptides that are capable of engaging in a variety of potential hydrophobic or hydrogen-bonding interactions with receptor moieties, with the expectation of obtaining more potent antagonists or inverse agonists, or compounds with a mixed K agonist/u antagonist profile. In Specific Aim 2 we will substitute the Dhp analogues developed in Specific Aim 1 for Tyr1 in known selective Kappa-, delta- or mu-agonist opioid peptides to convert them into antagonists or inverse agonists with selectivity for Kappa-, delta- or mu-receptors and their subtypes. In Specific Aim 3 we will develop potent K opioid antagonists or inverse agonists through structural modification of the cyclic tetrapeptide c[Phe-D-Pro-Phe-(D,L)-Trp] (CJ-15,208) recently isolated from the fungus Ctenomyces serratus. In Specific Aim 4 we will identify opioid peptide analogues containing certain Dhp analogues developed under Specific Aim 1 that have a mixed K agonist/mu antagonist profile as potential agents for the treatment of cocaine abuse. Specific Aim 5 concerns the development of chimeric opioid peptides with a mixed mu agonist/delta antagonist profile as analgesics with a low propensity to produce tolerance and dependence. The in vitro opioid activity profiles will be determined by performing opioid receptor binding assays, the guinea pig ileum and mouse vas deferens assays, and the [35S]GTPgammaS binding assay. The characterization of some of the compounds in vivo will include determination of the effects on cocaine discrimination and self-administration for the K agonist/mu antagonists and analgesic testing, including tolerance and dependence development, for the mixed mu agonist/delta antagonists. The conformation(s) of select compounds will be examined by 1HNMRspectroscopy in conjunction with theoretical conformational analyses.

描述（由申请人提供）：我们建议将有效，稳定和可生物利用的阿片类肽类似物构成i）i）拮抗剂或反向激动剂，对MU-或Kappa- opioid受体具有很高的选择性，及其子类型及其子类型作为药理学工具以及II）的apioid apioid Agnogagogiant for Agagogrogibers/aigogagogrip for Agagogrips/ii II II型。为了实现这些目标，我们使用跨学科方法，其中包含有机合成，肽化学，广泛的药理特征和构象研究。具体目标1是基于我们最近发现的，即在阿片类药物肽中取代3-（2,6-二甲基-4-羟基苯基）丙酸（DHP）替代N端酪氨酸残基可在Mu-，delta-或kappa-recectors上产生拮抗剂。我们将在阿片类肽中合成DHP类似物，以便能够与受体部分进行各种潜在的疏水性或氢键相互作用，并期望获得更多有效的拮抗剂或更有效的拮抗剂或混合k Agonist/U型抗体抗体介质。在特定目标2中，我们将在特定目标1中为Tyr1中开发的DHP类似物在已知的选择性kappa-，delta-或mu-agyist阿片类肽中以具有选择性的kappa-，delta或mu-peptors及其子类型的拮抗剂或逆激动剂。在特定的目标3中，我们将通过对最近从真菌Ctenomyces Serratus分离的环环四肽C [phe-d-d-pro-phe-（d，l）-trp]（d，l）-trp]（d，l）-trp]（d，l）-trp]（d，l）-trp]（d，l）-trp]（d，l）-trp]（CJ-15,208）来发展有效的K阿片类拮抗剂或反激动剂。在特定目的4中，我们将确定包含在特定目标1下开发的某些DHP类似物的阿片类肽类似物，这些DHP类似物具有混合k激动剂/MU拮抗剂概况作为治疗可卡因滥用的潜在药物。具体目的5涉及与混合Mu激动剂/三角洲拮抗剂概况的嵌合阿片类肽的发展，作为镇痛药，其倾向较低，可产生耐受性和依赖性。体外阿片类药物活性谱将通过执行阿片受体结合测定，豚鼠回肠和小鼠VAS递延测定法以及[35S] Gtpgammas结合测定法来确定。某些化合物在体内的表征将包括确定对可卡因歧视的影响和对K激动剂/MU拮抗剂和镇痛测试的影响，包括对混合MU激动剂/Delta拮抗剂的耐受性和依赖性发展。精选化合物的构象将通过1HNMRSPECTROSCOPOCOPOS与理论构象分析一起检查。