Preclinical Identification of Better Antimuscarinic Antidepressants

更好的抗毒蕈碱抗抑郁药的临床前鉴定

• 批准号: 9521089
• 负责人: james H Woods
• 金额: $ 59.08万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-15 至 2019-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9521089
• 关键词: Adverse effects; Affinity; Agonist; Animals; Anti-Cholinergics; Antidepressive Agents; Arecoline; Attention; Basic Science; Behavior; Behavioral; Binding; Biological Assay; Brain; Cardiovascular system; Chemical Models; Chemical Structure; Chemicals; Cholinergic Agents; Clinical; Cognitive; Cognitive deficits; Data; Dementia; Depressed mood; Disadvantaged; Dose; Evaluation; Goals; Hand; Human; Impaired cognition; In Vitro; Individual; Lead; Learning; Ligands; Literature; Measures; Mediating; Memory; Memory impairment; Mental Depression; Modeling; Modification; Muscarinic Acetylcholine Receptor; Muscarinic Agonists; Muscarinic Antagonists; Muscarinic M1 Receptor; Muscarinics; Outcome; Patients; Penetration; Peripheral; Pharmaceutical Preparations; Pharmacology; Phase; Procedures; Process; Rat Strains; Rattus; Reporting; Sampling; Scopolamine; Series; Stimulus; Synthesis Chemistry; Technology; Testing; To specify; Training; Wood material; Work; antidepressant effect; base; clinically relevant; cognitive function; cognitive performance; cognitive testing; depressive symptoms; design; drug candidate; drug synthesis; improved; in vitro Assay; in vivo; noradrenergic; novel; pre-clinical; public health relevance; receptor; reuptake; sedative; touchscreen; translational study; vigilance

 DESCRIPTION (provided by applicant): The recent reports that scopolamine has antidepressant effects in humans has raised the hope that this antimuscarinic drug represents an improvement over the serotonergic and noradrenergic reuptake blockers that have formed the basis for antidepressant medication for decades. Scopolamine's effects had a rapid onset of action, and were quite long lasting, giving them considerable advantage over previous medications. Of concern for the use of scopolamine in the treatment of depression is that scopolamine is used extensively in both human and animal studies to model cognitive deficits and dementia. There is, therefore, the likelihood that the antidepressant effects of scopolamine will coexist with the drug's well-known detrimental effects on attention, learning, and memory. The hypothesis on which the current proposal is based is that these two effects can be separated. They may, for example, be mediated by distinct receptor subtypes or by different efficacies at those receptors. Our plan is to evaluate selected antimuscarinic drugs in a series of coordinated assays designed to understand their profiles of activity. The assays will begin with in vivo evaluations to ascertain if a drug is a muscarinic antagonist centrally and peripherally. I so, its effects in antidepressant, and learning and memory assays will be described, and if a significantly smaller dose is necessary to produce antidepressant-like effects than to disrupt cognitive performance, its affinity and efficacy at the five muscarinic receptor subtypes will be measured. This will determine whether it is selectivity at one or more receptor subtype that confers antidepressant effects with reduced anti-cognitive effects. Chemical modeling will be applied to candidate compounds in attempts to improve their spectrum of activity so that there is an even greater pharmacological distinction between the desired and the off-target effects. Data obtained with our lead compound, L687,306 encourage our attempts to pursue this goal. According to the literature, L 687,306 is an M2 and M3 antagonist, has very slight efficacy at the M1 receptor, and is able to ameliorate the effects of scopolamine in cognitive tests. In our assays, it blocks the cardiovascular effects of arecoline, has discriminative stimulus effects in common with scopolamine, and is as active as scopolamine in the antidepressant assay. It is distinct from scopolamine in that it does not suppress ongoing behavior even at large doses, and it is able to competitively antagonize the suppressant effects of arecoline, which scopolamine cannot do. We anticipate that L 687,306 will have little effect on memory and attention until large doses are administered, since this drug has very little sedative effect and antagonizes scopolamine's anticognitive effects in similar assays. In vitro assays will indicate how the binding profile of L 687,306 differs from that of scopolamine, and on this basis, chemical modeling will be applied to improve on the presumed critical distinction. Through this process, we anticipate being able to specify the receptor mechanisms by which muscarinic antagonists ameliorate depression, how these are distinct from those that lead to impaired cognition, and to designate chemical entities that are likely to have an improved profile of antidepressant activity.

 描述（由适用提供）：最近的报道表明，scopolamine在人类中具有抗抑郁作用，这使人们希望这种抗毒性药物代表了对塞拉顿能和去甲肾上腺素能的再摄取阻滞剂的改善，这已经构成了数十年来抗抑郁药的基础。 Scopolamine的作用迅速发挥作用，并且持久持久，使它们在以前的药物上具有很大的优势。人们关注的是在抑郁症治疗抑郁症中的关注是，在人类和动物研究中广泛使用了Scopolamine来模拟认知定义和痴呆症。因此，海pol碱的抗抑郁作用可能与该药物对注意力，学习和记忆的有害影响共存的可能性。当前提案所基于的假设是可以分开这两种效应。例如，它们可以通过不同的受体亚型或在这些受体的不同效果介导。我们的计划是在一系列 旨在了解其活动概况的协调测定。这些测定将从体内评估开始，以确定药物是否是毒蕈碱拮抗剂，也可能是最有可能的。我因此，将描述其在抗抑郁药中的作用，学习和记忆测定法，如果要产生抗抑郁药样效果比破坏认知性能要小得多，则将测量其在五个毒蕈碱接收器亚型的相关性和有效性。这将确定是否在一个或多个接收器亚型下选择抗抑郁作用并降低抗认知作用的选择性。化学建模将应用于候选化合物，以改善其活性范围，以使所需的和脱靶效应之间存在更大的药理区别。使用我们的铅化合物获得的数据L687,306鼓励我们追求这一目标的尝试。根据文献，L 687,306是M2和M3拮抗剂，在M1受体方面具有非常小的效率，并且能够改善Scopolamine在认知测试中的影响。在我们的评估中，它阻止了跨雷素的心血管效应，具有歧视性刺激作用，与scopolamine共同，并且在抗抑郁测定中与copolamine一样活跃。它与东pol碱不同，因为它即使在很大的剂量下也不会抑制持续的行为，并且能够能够胜任地层氨基氨基氨酸的抑制作用，而北极蛋白无法做到。我们预计L 687,306对记忆和注意力的影响几乎没有影响，直到给药大剂量，因为该药物的镇静作用很小，并且在类似测定中拮抗了Scopolamine的抗认知作用。体外测定法将表明L 687,306的结合曲线与Scopolamine的结合分布如何不同，在此基础上，化学建模将用于改进所提出的关键疾病。通过这一过程，我们预计能够指定毒蕈碱拮抗剂改善抑郁症的接收器机制，这些机制与导致认知受损的抑郁症有何不同，并指定了可能改善抗抑郁活性概况的化学实体。