Synthesis of Alpha2/Alpha3 GABA Agonists to Treat Neuropathic Pain

合成 Alpha2/Alpha3 GABA 激动剂治疗神经性疼痛

• 批准号: 8435779
• 负责人: James M Cook
• 金额: $ 31.84万
• 依托单位: UNIVERSITY OF WISCONSIN MILWAUKEE
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-01 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8435779
• 关键词: Acquired Immunodeficiency Syndrome; Address; Adverse effects; Agonist; Amnesia; Analgesics; Anti-Anxiety Agents; Anxiety Disorders; Ataxia; Back Pain; Behavioral; Benzodiazepines; Biological; Brain; Central Nervous System Diseases; Chronic; Clinical; Clinical Trials; Constipation; Convulsions; Data; Development; Diabetic Neuropathies; Diffuse; Discrimination; Disease; Drug Prescriptions; Evaluation; Exhibits; Foundations; Functional disorder; GABA Agonists; Goals; Heart; Hepatotoxicity; Human; Hyperalgesia; Hypersensitivity; International; Lead; Ligands; Light; Mediating; Medical; Mental Depression; Metabolic; Migraine; Modeling; Modification; Monkeys; Morphine; Mus; Muscle; Narcotic Antagonists; Nervous system structure; Neuraxis; Neuropathy; Neuropharmacology; New Agents; Nociception; Operative Surgical Procedures; Opioid Analgesics; Outcome; PTGS2 gene; Pain; Painless; Paraplegia; Parents; Patients; Peripheral; Phantom Limb Pain; Pharmaceutical Preparations; Physiological Processes; Population; Postherpetic neuralgia; Productivity; Property; Qualifying; Quality of life; Quantitative Structure-Activity Relationship; Rattus; Research; Rodent; Sedation procedure; Sensory; Series; Spinal Cord; Stimulus; Structure; Syndrome; Tissues; Toxic effect; Work; addiction; allodynia; animal efficacy; base; cancer pain; design; drug candidate; gamma-Aminobutyric Acid; improved; in vivo; inflammatory neuropathic pain; inflammatory pain; inhibitor/antagonist; knowledge base; nerve injury; novel; novel strategies; pain receptor; painful neuropathy; productivity loss; receptor; scaffold; sedative; spontaneous pain; tool

DESCRIPTION (provided by applicant): Neuropathic pain encompasses a range of painful conditions of diverse origins including diabetic neuropathy, post-herpetic neuralgia and nerve injuries after surgery. It includes pain following paraplegia, hypersensitivity to non-painful stimli (allodynia), for example after surgery or during migraine attacks, spontaneous pain, hyperalgesia and diffuse muscle tenderness of myofacial syndromes. Back pain, cancer pain and AIDS associated pain also qualify as neuropathic pain. Currently prescribed drugs for neuropathic pain are often addictive, are not effective for all patients and have various side effects including tolerance, addiction, sedation, liver toxicity. The financial burden from the los of productivity in the US alone numbers in the billions of dollars notwithstanding the misery these patients suffer. Recently, we have discovered a series of nonsedating alpha2/alpha3 BzR/GABA (A) agonists that are active against neuropathic pain as well as anxiety disorders and convulsions. These agents do not develop tolerance and are comprised of a privileged scaffold (imidazobenzodiazepine), the result of which has less chance for toxicity. Because they exhibit little or no efficacy at a1 and a5 subtypes, they will exhibit very little or no abuse potential. This research centers on the modification of these new agents to prolong duration of action in vivo and to provide better subtype selectivity at either a2 or a3 BzR/GABA(A)ergic subtypes. This would preclude the origin of side effects including sedation, ataxia, amnesia, tolerance and abuse potential. In addition, this work will help to establish which GABAerigc subtype in the spinal cord is the nociceptive target of choice. An eventual goal is to replace the addictive opioid analgesics with these safer, non addictive ligands for treatment of all types of neuropathic and inflammatory pain, in human populations. PUBLIC HEALTH RELEVANCE: The design and development of new nonsedating, nonaddictive agents to treat neuropathic pain is under study. These agents are designed to treat diabetic neuropathy, post-herpetic neuralgia, phantom limb pain, pain from nerve injuries after surgery. This includes pain after paraplegia, hypersensitivity to non-painful stimuli (allodynia) and migraine attacks. It is felt these agents will also be effective in back pain, cancer pain and AIDS associated pain without the side effects of morphine (including addiction) or of COX-2 inhibitors (heart problems). There is a significant unmet need for new drugs to treat neuropathic pain. The financial burden from the loss of productivity in the US alone numbers in the billions of dollars, notwithstanding the misery these patients must endure.

描述（由申请人提供）：神经性疼痛包括一系列痛苦的起源疾病，包括糖尿病神经病，治疗后神经痛和手术后神经损伤。它包括瘫痪后的疼痛，对非疗法刺激的超敏反应（异常性刺激），例如手术后或偏头痛发作期间，自发疼痛，痛苦和肌膜综合征的弥漫性肌肉压痛。背部疼痛，癌症疼痛和辅助疼痛也可以作为神经性疼痛。目前，处方的神经性疼痛药物通常会上瘾，对所有患者都不有效，并且具有各种副作用，包括耐受性，成瘾，镇静，肝毒性。尽管这些患者遭受的痛苦，但仅美国生产力的财务负担数十亿美元。最近，我们发现了一系列非替代的alpha2/alpha3 bzr/gaba（A）激动剂，它们对神经性疼痛以及焦虑症和抽搐有效。这些代理人不产生耐受性，而是由特权支架（imidazobenzodiazepine）组成，其结果的毒性机会较小。由于它们在A1和A5亚型上表现出很少或没有功效，因此它们的滥用潜力很少或没有。这项研究集中于这些新药物在体内延长作用持续时间的修饰，并在A2或A3 BZR/GABA（A）ERGIC亚型下提供更好的亚型选择性。这将排除副作用的起源，包括镇静，共济失调，健忘症，宽容和滥用潜力。此外，这项工作将有助于确定脊髓中的哪种Gabaerigc亚型是选择的伤害性靶标。最终的目标是用这些更安全的，非上瘾的配体代替成瘾性的阿片类镇痛药，以治疗人群中所有类型的神经性疼痛和炎症性疼痛。 公共卫生的相关性：正在研究新的非义务，非副作用的药物的设计和开发。这些药物旨在治疗糖尿病神经病，脊髓神经痛，幻影肢体疼痛，手术后神经损伤疼痛。这包括截瘫后的疼痛，对非生育刺激（异常性疾病）和偏头痛攻击的过敏性。人们认为，这些药物也将在背痛，癌症疼痛和辅助疼痛的情况下有效，而没有吗啡（包括成瘾）或COX-2抑制剂（心脏问题）的副作用。新药对治疗神经性疼痛的需求很大。仅美国在数十亿美元的生产力损失中，财务负担 美元，尽管这些患者必须忍受痛苦。