BIFUNCTIONAL OPIOID PEPTIDE ANALGESICS

双功能阿片肽镇痛药

• 批准号: 7643822
• 负责人: PETER W SCHILLER
• 金额: $ 10.77万
• 依托单位: CLINICAL RESEARCH INSTITUTE OF MONTREAL
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-07-01 至 2010-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7643822
• 关键词: Absence of pain sensation; Academia; Acute Pain; Adverse effects; Agonist; Analgesics; Award; Binding; Binding Sites; Biological; Biological Assay; Biological Availability; Blood - brain barrier anatomy; Brain; Cannabinoids; Cells; Clinical; Constipation; Dependence; Development; Docking; Drug Design; Drug Kinetics; GTP Binding; Gastrointestinal Transit; Half-Life; Human; In Vitro; Industry; Ligands; Link; Mediating; Medicine; Membrane; Modeling; Molecular Models; Morphine; Narcotic Antagonists; Neuraxis; ORL1 receptor; Opiates; Opioid; Opioid Analgesics; Opioid Peptide; Opioid Receptor; Oral; Pain; Pathway interactions; Peptide Synthesis; Peptides; Pharmacodynamics; Phase; Physical Dependence; Preparation; Property; Rattus; Reporting; S Phase; Site; Solid; Solutions; Structure-Activity Relationship; Substance P; Tail; Techniques; Tissues; Ventilatory Depression; addiction; base; chronic constriction injury; conditioning; design; drug development; evidence base; functional group; in vivo; lysylphenylalanine; molecular modeling; novel; painful neuropathy; pharmacophore; phenylalanylarginine; receptor; receptor binding

DESCRIPTION (provided by applicant): There is an urgent clinical need for the development of opioid analgesics with novel biological activity profiles that lack the limiting side effects of the currently available opiates. It has been shown that the propensity of ¿ opioid agonists to produce analgesic tolerance and physical dependence can be reduced by co-administration of a d opioid antagonist, a cannabinoid (CB1) antagonist, a substance P (NK1) antagonist or an opioid receptor like (ORL1) antagonist. On the basis of this evidence we propose to develop systemically active, bifunctional compounds with a mixed ¿ opioid agonist/d opioid antagonist-, ¿ agonist/CB1 antagonist-, ¿ agonist/NK1 antagonist- or ¿ agoist/ORL1 antagonist profile as analgesics expected to produce little or no tolerance and physical, dependence, and with low addiction liability. Bifunctional ligands with these profiles that are systemically active and able to cross the blood-brain barrier (BBB) have not been reported to date. The design of the bifunctional ligands will be based on attachment of the various antagonist pharmacophores (peptides and non-peptides) to various sites of the potent and highly selective ¿ opioid agonist peptide [Dmt1]DALDA (H-Dmt-D-Arg-Phe-Lys-NH2; Dmt = 2'6'- dimethyltyrosine) either directly or via a short linker in a way that does not interfere with the agonist/antagonist properties of the two components. This will be done by careful consideration of known structure-activity relationships (SAR) of the two components in conjunction with molecular modeling of ligand docking to the receptor binding sites. [Dmt1]DALDA was chosen as the ¿ agonist component because of its high analgesic potency, oral bioavailability, high stability, long elimination half-life and long duration of action. There is evidence to indicate that the proposed [Dmt1]DALDA-antagonist conjugates will be able to penetrate into the central nervous system because the [Dmt1]DALDA component will confer blood-brain barrier crossing ability upon the entire bifunctional construct. This has been shown to be the case with two already prepared ¿ opioid agonist/d antagonists of this type which produced potent centrally mediated antinociception when given subcutaneously (s.c.). The bifunctional ligands will be prepared by solid-phase synthesis or by a combination of solid-phase- and solution peptide synthesis techniques. The in vitro biological profiles of the compounds will be determined by performing receptor binding assays, isolated tissue assays and [35S]GTP?S binding assays using HEK cells containing singly expressed ¿ opioid, d opioid, CB1, NK1, or ORL1 receptors. Their analgesic potencies will be determined in acute pain models (tail-flick and hot plate) and in the chronic constriction injury model as a model of neuropathic pain. Furthermore, the propensities of the compounds to produce analgesic tolerance, physical dependence, addiction (place conditioning paradigm), constipation and respiratory depression will be examined.

描述（由适用提供）：具有新型生物学活性曲线的阿片类镇痛药的急需临床需求，这些型生物学活性谱缺乏当前可用的阿片类药物的限制副作用。已经表明，通过共同给予阿片类药物拮抗剂，大麻素（CB1）拮抗剂，一种物质P（NK1）拮抗剂或类似（ORL1）拮抗剂（ORL1）拮抗剂，可以降低阿片类药物激动剂产生镇痛耐受性和身体依赖性的承诺。在此证据的基础上，我们建议开发具有混合的酚类化合物/D型卵巢剂/D杀节性拮抗剂，»agonist/cb1拮抗剂，«agonist/nk1拮抗剂或eogogoganist/nk1拮抗剂或eogogogisist/orl1拮抗剂，因为预期的镇痛症和物理性依赖性和物理不相关，且依赖性和物理性依赖性和物理性依赖性和物理性不足。迄今为止尚未报道具有系统活跃且能够越过血脑屏障（BBB）的双功能配体。 The design of the bifunctional ligands will be based on attachment of the various antagonist pharmacophores (peptides and non-peptides) to various sites of the potential and highly selective ¿ oopioid agonist peptide [Dmt1]DALDA (H-Dmt-D-Arg-Phe-Lys-NH2; Dmt = 2'6'- dimethyltyrosine) either directly or via a short linker in a way that不会干扰两个组成部分的激动剂/拮抗剂。这将通过仔细考虑这两个组件的已知结构 - 活性关系（SAR）以及配体对接收器结合位点的分子建模结合使用。 [DMT1] Dalda因其高镇痛效力，口服生物利用度，高稳定性，较高的紧急半衰期和长时间的作用而被选为Anmonist成分。有证据表明，所提出的[DMT1] Dalda-Antagonist偶联者将能够穿透中枢神经系统，因为[DMT1] DALDA成分将赋予整个双功能构建体的血脑屏障交叉。已经证明，这种类型的两种已经制备的 - 阿片类药物激动剂/D拮抗剂是这种情况，当皮下给予时，该拮抗剂会产生有效的中心介导的抗伤害感受（S.C.）。双功能配体将通过固相合成或结合固相和溶液肽合成技术制备。这些化合物的体外生物学特征将通过执行受体结合测定，孤立的组织测定和[35S] GTP的结合测定法，使用单独表达的HEK细胞进行»opioid，d opoioid，d opioid，cb1，nk1，nk1或orl1受体。它们的镇痛作用将在急性疼痛模型（尾部和热板）以及慢性收缩损伤模型中确定，作为神经性疼痛的模型。此外，将检查化合物产生镇痛耐受性，物理依赖性，成瘾（位置调节范式），便秘和呼吸抑制的特性。