CB1/CB2 Cannabinoid Ligands for HIV Neuropathic Pain

摘要 许多感染艾滋病毒的患者会发展为远端对称性神经病变，常伴有 疼痛。在一些患者中，艾滋病毒抗逆转录病毒治疗可能会引发并加剧神经病理性疼痛。其作用机制 潜在的HIV神经病理性疼痛(HIVNP)尚不清楚。HIVNP对治疗相对耐药 通常用于其他类型的神经性疼痛(例如，再摄取阻滞剂、加巴喷丁)。临床上 在HIVNP中已经报告了烟熏大麻的显著影响，这表明大麻类活动可能 为这些患者提供显著的止痛益处。首先，我们将开发新型CB2激动剂，不含或非常 CB1的低功能疗效，基于AM1710化学型的改进的药理学特征。这些 新化合物将成为有效的CV2激动剂和中性的CB1拮抗剂。第二种方法将涉及 新型外周作用CB1/CB2激动剂的设计与合成。我们将设法获得小说 优化了CB2/CB1对HIVNP各自影响的化合物。我们有 结果表明，本实验室研制的选择性CB2激动剂AM1710在大鼠模型中具有镇痛作用。 HIVNP。我们认为CB2激动剂可以被证明是一种有效的非成瘾治疗策略。 HIVNP，并可能用于其他慢性疼痛情况。我们提出了两种方法。这两种方法都将 开发包含设计控制的大麻素失活的新型配体，这是最近开发的一个概念 在我们的实验室里检测大麻能化合物。这涉及到在血清的每个配基中引入 酯酶敏感部分，当受到酶的水解作用时，改变分子 变成不活跃的代谢物。新化合物在体内的作用时间由该化学物质控制。 固着基团的性质和环境，以及新化合物的受制程度 对于仓库效应，这是一种主要由化合物的疏水性控制的性质。该项目将涉及 1)新型配体的设计和合成；2)CB2和CB1的体外表征 亲和力和功能潜力，以及它们的生化稳定性，或生物利用度，和能力(或缺乏 跨越血脑屏障。将对成功的化合物进行筛选(生化核心)，以确定其 对炎性疼痛模型的影响。3)将测试选定数量的化合物对HIV的有效性 神经病理性疼痛模型的副作用、耐受性和潜在的滥用倾向。

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.