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）：神经性疼痛涵盖一系列不同来源的疼痛病症，包括糖尿病性神经病、带状疱疹后神经痛和手术后神经损伤。它包括截瘫后的疼痛、对非疼痛刺激的过敏（异常性疼痛），例如手术后或偏头痛发作期间、自发性疼痛、痛觉过敏和肌面综合征的弥漫性肌肉压痛。背痛、癌症疼痛和艾滋病相关疼痛也属于神经性疼痛。目前用于治疗神经性疼痛的处方药物通常具有成瘾性，并非对所有患者都有效，并且具有各种副作用，包括耐受性、成瘾性、镇静性、肝毒性。尽管这些患者遭受着痛苦，但仅在美国，生产力损失所造成的经济负担就达数十亿美元。最近，我们发现了一系列非镇静性 alpha2/alpha3 BzR/GABA (A) 激动剂，可有效对抗神经性疼痛以及焦虑症和惊厥。这些药物不会产生耐受性，并且由特殊的支架（咪唑并苯二氮卓）组成，因此产生毒性的可能性较小。因为它们对 a1 和 a5 亚型表现出很少或没有功效，所以它们表现出很少或没有滥用潜力。这项研究的重点是对这些新药物进行修饰，以延长体内作用持续时间，并为 a2 或 a3 BzR/GABA(A) 能亚型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、耐受性和滥用可能性。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目标。最终目标是用这些更安全、非成瘾性配体取代成瘾性阿片类镇痛药，用于治疗人类所有类型的神经性疼痛和炎症性疼痛。 公共健康相关性：用于治疗神经性疼痛的新型非镇静、非成瘾药物的设计和开发正在研究中。这些药物旨在治疗糖尿病神经病变、带状疱疹后神经痛、幻肢痛、手术后神经损伤引起的疼痛。这包括截瘫后的疼痛、对非疼痛刺激的过敏（异常性疼痛）和偏头痛发作。人们认为这些药物对背痛、癌症疼痛和艾滋病相关疼痛也有效，而且没有吗啡（包括成瘾）或 COX-2 抑制剂（心脏问题）的副作用。治疗神经性疼痛的新药的需求尚未得到满足。仅美国生产力损失造成的经济负担就达数十亿美元 美元，尽管这些病人必须忍受痛苦。