CB1/CB2 Cannabinoid Ligands for HIV Neuropathic Pain

CB1/CB2 大麻素配体治疗 HIV 神经性疼痛

• 批准号: 9073239
• 负责人: Alexandros Makriyannis
• 金额: $ 13.36万
• 依托单位: UNIVERSITY OF ARIZONA
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-05-01 至 2022-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9073239
• 关键词: Absence of pain sensation; Acute inflammatory pain; Adverse effects; Affinity; Agonist; Anabolism; Analgesics; Anti-Inflammatory Agents; Anti-inflammatory; Biochemical; Biological Availability; Blood - brain barrier anatomy; Brain; CNR1 gene; CNR2 gene; Cannabinoids; Cannabis; Categories; Characteristics; Chemicals; Cyclic AMP; Development; Distal; Drug abuse; Endocannabinoids; Environment; Enzymes; Euphoria; Evaluation; Family; G-Protein-Coupled Receptors; Generations; HIV; HIV antiretroviral; HIV therapy; Human; Hydrophobicity; In Vitro; Laboratories; Lead; Ligands; Mediating; Memory; Metabolic Biotransformation; Methods; Modality; Modeling; Motivation; Mus; Nature; Neuraxis; Neuropathy; Pain; Pain management; Patient Agents; Patients; Peripheral; Pharmaceutical Preparations; Pharmacology; Pharmacotherapy; Plasma; Preparation; Production; Property; Rattus; Reporting; Resistance; Rewards; Serum; Smoke; Testing; addiction; analog; anandamide; base; chronic pain; clinically significant; common treatment; design; endogenous cannabinoid system; esterase; improved; in vivo; inflammatory pain; lipophilicity; liquid chromatography mass spectrometry; novel; novel therapeutics; painful neuropathy; prototype; reuptake; synergism

Abstract Many patients suffering from HIV will develop distal symmetrical neuropathy that is frequently accompanied by pain. In some patients, HIV antiretroviral treatments can elicit and exacerbate neuropathic pain. The mechanisms underlying HIV neuropathic pain (HIVNP) are not well understood. HIVNP is relatively resistant to treatments commonly used for other types of neuropathic pain (e.g., reuptake blockers, gabapentinoids). Clinically significant effects of smoked cannabis have been reported in HIVNP, suggesting that cannabinoid activity may provide significant analgesic benefit in these patients. First, we shall develop novel CB2 agonists with no or very low functional efficacy for CB1, with improved pharmacological profiles based on the AM1710 chemotype. These novel compounds will be potent CV2 agonists and neutral CB1 antagonists. The second approach will involve the design and synthesis of novel CB1/CB2 agonists that are peripherally acting. We shall seek to obtain novel compounds in which the CB2/CB1 contributions to their respective effects on HIVNP is optimized. We have shown that AM1710, a selective CB2 agonist developed in our laboratory, elicits analgesic actions in a model of HIVNP. We propose that CB2 agonists could prove to be an effective strategy for non-addictive treatment of HIVNP and possibly for other chronic pain conditions. We propose two approaches. Both approaches will develop novel ligands that encompass design controlled cannabinoid deactivation, a concept recently developed in our laboratory for cannabinergic compounds. This involves the introduction within each ligand of a serum esterase susceptible moiety, which when subjected to the enzyme’s hydrolytic action, transforms the molecule into inactive metabolites. The duration of action in vivo of the new compounds is controlled by the chemical nature and environment of the sessile group, as well as by the degree to which the novel compound is subject to a depot effect, a property largely controlled by the compound’s hydrophobic character. The project will involve 1) the design and synthesis of the novel ligands and 2) in vitro characterization evaluation for their CB2 and CB1 affinities and functional potencies, as well as their biochemical stabilities, or bioavailabilities, and abilities (or lack of) to cross the blood brain barrier. The successful compounds will be screened (Biochemical Core) for their effects in models of inflammatory pain. 3) A select number of compounds will be tested for their efficacy in a HIV neuropathic pain model for their side effects, tolerance, and potential abuse liability.

摘要 许多患有HIV的患者将发展远端对称性神经病，其经常伴随有 痛苦在一些患者中，HIV抗逆转录病毒治疗可引发和加剧神经性疼痛。的机制 潜在的HIV神经性疼痛（HIVNP）尚未得到很好的理解。HIVNP对治疗相对耐药 通常用于其它类型的神经性疼痛（例如，再摄取阻断剂、加巴喷丁类）。临床 据报道，吸食大麻对HIVNP有显著影响，这表明大麻素活性可能 在这些患者中提供显著的镇痛益处。首先，我们将开发新的CB 2激动剂， CB 1的功能功效低，基于AM 1710化学型具有改善的药理学特征。这些 新型化合物将成为有效的CV 2激动剂和中性CB 1拮抗剂。第二种方法将涉及 外周作用的新型CB 1/CB 2激动剂的设计和合成。我们将寻求获得新的 化合物，其中CB 2/CB 1对它们各自对HIVNP的作用的贡献被优化。我们有 表明我们实验室开发的选择性CB 2激动剂AM 1710在一种模型中具有镇痛作用， HIVNP。我们认为CB 2激动剂可能被证明是一种有效的非成瘾性治疗策略， HIVNP和可能用于其他慢性疼痛状况。我们提出两种方法。这两种方法将 开发新的配体，包括设计控制的大麻素失活，这是最近开发的概念 大麻能化合物的研究这包括在每个配体中引入血清 酯酶敏感部分，当受到酶的水解作用时，将分子 转化为无活性代谢物新化合物在体内的作用持续时间由化学物质控制。 性质和环境的固着基团，以及在何种程度上，新的化合物是受 储存效应，一种主要由化合物的疏水特性控制的特性。该项目将涉及 1)新型配体的设计与合成; 2）新型配体CB 2和CB 1的体外表征评价 亲和力和功能效力，以及它们的生物化学稳定性，或生物利用度，和能力（或缺乏 的）以穿过血脑屏障。成功的化合物将被筛选（生化核心），以确定其 在炎症性疼痛模型中的作用。3)将测试选定数量的化合物在HIV中的功效。 神经病理性疼痛模型的副作用，耐受性和潜在的滥用倾向。