BIFUNCTIONAL OPIOID PEPTIDE ANALGESICS

双功能阿片肽镇痛药

• 批准号: 7513568
• 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/7513568
• 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; Morphine; Narcotic Antagonists; Neuraxis; Numbers; 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; concept; conditioning; design; drug development; 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（由申请人提供）：临床上迫切需要开发具有新型生物活性特征的阿片类镇痛药，这些阿片类镇痛药缺乏目前可用阿片类药物的限制性副作用。已经表明，通过共同施用阿片样物质拮抗剂、大麻素（CB 1）拮抗剂、P物质（NK 1）拮抗剂或阿片样受体样（ORL 1）拮抗剂，可以降低阿片样物质激动剂产生镇痛耐受性和身体依赖性的倾向。在此证据的基础上，我们建议开发具有全身活性的双功能化合物，其具有混合的阿片激动剂/阿片拮抗剂-、激动剂/CB 1拮抗剂-、激动剂/NK 1拮抗剂-或激动剂/ORL 1拮抗剂特征，作为预期产生很少或没有耐受性和身体依赖性并且具有低成瘾倾向的镇痛剂。具有这些特征的双功能配体具有全身活性并且能够穿过血脑屏障（BBB），迄今为止尚未报道。双功能配体的设计将基于各种拮抗剂药效团（肽和非肽）以不干扰两种组分的激动剂/拮抗剂性质的方式直接或通过短接头连接到有效和高选择性阿片样物质激动剂肽[Dmt 1]DALDA（H-Dmt-D-Arg-Phe-Lys-NH 2; Dmt = 2 '6'-二甲基酪氨酸）的各个位点。这将通过仔细考虑两种组分的已知结构-活性关系（SAR）以及配体与受体结合位点对接的分子建模来完成。[Dmt 1]选择DALDA作为激动剂组分，因为其镇痛效力高，口服生物利用度高，稳定性高，消除半衰期长，作用持续时间长。有证据表明，所提出的[Dmt 1] DALDA-拮抗剂缀合物将能够渗透到中枢神经系统中，因为[Dmt 1]DALDA组分将赋予整个双功能构建体穿过血脑屏障的能力。这已经被证明是两种已经制备的这种类型的阿片激动剂/拮抗剂的情况，当皮下（s.c.）给药时，它们产生了有效的中枢介导的抗伤害感受。双官能配体将通过固相合成或通过固相和溶液肽合成技术的组合来制备。化合物的体外生物学特性将通过进行受体结合试验、分离组织试验和[35 S]GTP？使用含有单一表达的阿片样物质、阿片样物质、CB 1、NK 1或ORL 1受体的HEK细胞进行S结合试验。将在急性疼痛模型（甩尾和热板）和作为神经性疼痛模型的慢性压迫性损伤模型中测定其镇痛效力。此外，还将检查化合物产生镇痛耐受性、身体依赖性、成瘾性（位置调节范例）、便秘和呼吸抑制的倾向。