BIFUNCTIONAL OPIOID PEPTIDE ANALGESICS

双功能阿片肽镇痛药

基本信息

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
项目类别：
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

项目摘要

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）：临床迫切需要开发具有新型生物活性特征的阿片类镇痛药，且该类镇痛药没有目前可用的阿片类药物的有限副作用。在此基础上合用d阿片拮抗剂、大麻素(CB1)拮抗剂、P物质(NK1)拮抗剂或阿片受体样(ORL1)拮抗剂可减少阿片类激动剂产生的镇痛耐受性和身体依赖性。我们建议开发具有混合 ¿ 的系统活性双功能化合物的证据阿片类激动剂/d 阿片类拮抗剂-, ¿激动剂/CB1拮抗剂-, ¿激动剂/NK1拮抗剂-或¿ agoist/ORL1拮抗剂作为镇痛药，预计不会产生或很少产生耐受性和身体依赖性，并且具有低成瘾倾向，具有系统活性并能够穿过血脑屏障（BBB）的双功能配体。迄今为止已报道的双功能配体的设计将基于将各种拮抗剂药效团（肽和非肽）附着到有效且高度选择性的各个位点。阿片类激动剂肽 [Dmt1]DALDA（H-Dmt-D-Arg-Phe-Lys-NH2；Dmt = 2'6'-二甲基酪氨酸）直接或通过短接头以不干扰激动剂/拮抗剂的方式这将通过仔细考虑两种成分的已知结构-活性关系（SAR）以及配体与受体结合的分子模型来完成。 [Dmt1]DALDA 被选为 ¿激动剂成分，因为其镇痛效力高、口服生物利用度高、稳定性高、消除半衰期长和作用持续时间长。有证据表明，所提出的[Dmt1]DALDA-拮抗剂缀合物将能够渗透到中枢神经中。系统，因为 [Dmt1]DALDA 成分将赋予整个双功能结构穿越血脑屏障的能力，这已被证明是两个已经准备好的情况。这种类型的阿片类激动剂/d拮抗剂在皮下(s.c.)给予时产生有效的中枢介导的抗伤害作用。双功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。化合物的生物学特征将通过使用含有单表达 ¿ 的 HEK 细胞进行受体结合测定、分离组织测定和 [35S]GTP?S 结合测定来确定。阿片类药物、d 阿片类药物、CB1、NK1 或 ORL1 受体将在急性疼痛模型（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确定。将检查产生镇痛耐受性、身体依赖性、成瘾性（场所调节范式）、便秘和呼吸抑制的化合物。