Development of Mu Agonist Delta Antagonist Opioids as Analgesics for Chronic Pain

Mu 激动剂 Delta 拮抗剂阿片类药物作为慢性疼痛镇痛药的开发

基本信息

批准号：
9113533
负责人：
SUBRAMANIAM ANANTHAN
金额：
$ 87.99万
依托单位：
SOUTHERN RESEARCH INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-08-01 至 2020-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9113533
关键词：
Absence of pain sensation Acute Pain Adverse effects Affective Affinity Agonist Analgesics Behavioral Binding Bioavailable Biochemistry Biological Assay Biological Availability Brain Clinical Trials Computer Simulation Constipation Dependence Development Docking Dose Drug Design Drug Kinetics Drug usage Equilibrium Evaluation Exhibits Fentanyl Formulation Functional disorder Gastrointestinal Transit Generations Goals Guanosine Triphosphate Health Human Hydrocodone In Vitro Intestines Intravenous Knock-out Lead Libraries Ligands Light Liver Microsomes Mediating Medical Metabolic Methods Modeling Molecular Molecular Biology Morphinans Morphine Mus Narcotic Antagonists New England Opioid Opioid Analgesics Opioid Receptor Opioid Receptor Binding Oral Pain Patients Penetration Permeability Pharmaceutical Chemistry Pharmaceutical Preparations Pharmacology Pharmacotherapy Physical Dependence Preparation Process Property Protocols documentation Rattus Receptor Gene Research Research Institute Rodent Route Safety Solubility Structure Structure-Activity Relationship Testing Therapeutic Index Therapeutic Uses Universities Validation Ventilatory Depression absorption addiction analog aqueous base cell preparation chronic pain computational chemistry delta opioid receptor design drug candidate drug development drug discovery drug metabolism experience improved in vitro activity in vivo knock-down knockout gene lead series meetings metabolic profile mu opioid receptors novel pharmacophore pre-clinical radioligand receptor receptor function research study scaffold screening small molecule structural biology

项目摘要

DESCRIPTION (provided by applicant): Opioids such as morphine are the most potent and efficacious agents currently available for the treatment of moderate to severe acute and chronic pain. These drugs primarily act through the mu subtype of the opioid receptors. However, their therapeutic use is limited due to respiratory depression, opioid-induced bowel dysfunction, development of tolerance and dependence, and renewed concerns around addiction liabilities. There is an urgent unmet medical need for the discovery and development of novel analgesics that are as efficacious as morphine but devoid of significant side effects. Delta receptor gene knockout/knockdown experiments and studies using selective antagonists and bifunctional (mu agonist/delta antagonist) compounds have provided evidence that activation of mu receptor function with simultaneous suppression of delta receptor function produces analgesic effects with greatly diminished mu receptor mediated side effects. Thus, compounds possessing dual but opposing functional activity of mu receptor agonism and delta receptor antagonism have the potential to exhibit broad-spectrum analgesia with a wide safety margin and therapeutic index. Therefore, we have been pursuing the discovery of small molecules possessing the dual functional profile of mu agonism/delta antagonism. To this end, we recently discovered compounds possessing a balanced profile of high-affinity binding at mu and delta receptors and possessing mixed mu agonist/delta antagonist functional activity. In addition these compounds had a diminished propensity to produce tolerance, dependence and abuse liability. In this proposed project, our goal is to develop novel orally active mu agonist/delta antagonist compounds. The approach builds upon the structure-activity relationships determined for the lead series. The medicinal chemistry lead optimization strategy includes rational drug design utilizing crystal structure information on mu and delta receptors that became recently available as well as multi- parametric lead optimization for the improvement of physicochemical and pharmacokinetic properties. To achieve the goal of identifying lead preclinical candidates we will (1) design and synthesize new compounds based upon activity and in vitro pharmacokinetic properties (2) perform in vitro screening to determine opioid receptor binding and functional activity (3) determine the in vitro and in vivo pharmacokinetic profile (bioavailability, half-lifeand CNS levels) to select compounds for (4) comprehensive in vivo analgesic efficacy and side effect profiling in rodents. These goals will be accomplished through a collaborative effort involving a team with extensive experience in drug design, medicinal chemistry, computational chemistry, opioid biochemistry and molecular biology, pharmacokinetics, opioid pharmacology, and drug development.

描述（由适用提供）：如吗啡等阿片类药物是目前可用于治疗中度至重度急性和慢性疼痛的最潜在和有效的药物。这些药物主要通过阿片受体的MU亚型作用。但是，由于呼吸抑制，阿片类药物诱导的肠功能障碍，耐受性和依赖性的发展以及对成瘾责任的担忧，它们的治疗用途受到限制。紧急未满足的医疗需求是发现和开发新型镇痛药，这些镇痛药与吗啡一样有效，但没有显着的副作用。 Delta受体基因基因敲除/敲低实验和使用选择性厌氧菌和双功能（MU激动剂/Delta拮抗剂）化合物进行的研究提供了证据，表明MU受体功能的激活具有简单抑制Delta受体功能的激活，从而产生了肛门分析效应，并具有大大减少的MU受体受体介导的副作用。这是，我们一直在追求发现具有MU激动剂/Delta拮抗作用双重功能曲线的小分子。为此，我们最近发现了具有高亲和力结合在MU和Delta接收器的高亲和力结合的化合物，并具有混合的MU激动剂/Delta拮抗剂功能活性。此外，这些化合物的承诺降低了承诺，依赖性和滥用责任。在这个拟议的项目中，我们的目标是开发新颖的口服MU激动剂/Delta拮抗剂化合物。该方法建立在针对铅序列确定的结构活动关系的基础上。医学化学铅优化策略包括使用有关MU和Delta受体的晶体结构信息进行合理的药物设计，这些信息最近已获得，以及用于改善物理和药代动力学特性的多参数铅优化。 To achieve the goal of identifying lead preclinical candidates we will (1) design and synthesize new compounds based upon activity and in vitro pharmacokinetic properties (2) perform in vitro screening to determine opioid receptor binding and functional activity (3) determine the in vitro and in vivo pharmacokinetic profile (bioavailability, half-lifeand CNS levels) to select compounds for (4) comprehensive in vivo啮齿动物的镇痛效率和副作用分析。这些目标将通过在药物设计，药物化学，计算化学，OOID生物化学和分子生物学，药代动力学，OOID药理学和药物开发方面具有丰富经验的团队进行的协作努力来实现。