Preclinical Identification of Better Antimuscarinic Antidepressants

更好的抗毒蕈碱抗抑郁药的临床前鉴定

基本信息

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
项目类别：
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

项目摘要

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（由申请人提供）：最近关于东莨菪碱对人类具有抗抑郁作用的报道引发了人们的希望，即这种抗毒蕈碱药物代表了对血清素能和去甲肾上腺素再摄取阻滞剂的改进，这些阻滞剂已成为东莨菪碱数十年来抗抑郁药物作用的基础。起效迅速，且持续时间相当长，与以前使用东莨菪碱的药物相比，具有相当大的优势。东莨菪碱主要用于人类和动物研究中，以模拟认知缺陷和痴呆，因此，东莨菪碱的抗抑郁作用可能与该药物对注意力、学习、认知等方面的不良影响同时存在。当前提议所基于的假设是，这两种效应可以被分开，例如，它们可能是由不同的受体亚型或这些受体的不同功效介导的。评估一系列选定的抗毒蕈碱药物旨在了解其活性概况的协调测定开始于体内评估以确定药物是否是中枢和外周毒蕈碱拮抗剂，因此将描述其在抗抑郁药中的作用以及学习和记忆测定。与破坏认知能力相比，需要更小的剂量来产生抗抑郁样作用，将测量其对五种毒蕈碱受体亚型的亲和力和功效，这将确定它是否对一种或多种具有选择性。更多具有抗抑郁作用但抗认知作用减弱的受体亚型将应用于候选化合物，以尝试改善其活性范围，以便在预期效果和脱靶效果之间存在更大的药理学区别。用我们的先导化合物 L687,306 获得的结果鼓励我们尝试实现这一目标。根据文献，L 687,306 是一种 M2 和 M3 拮抗剂，对 M1 受体具有非常轻微的功效，并且能够改善东莨菪碱在认知测试中的作用，它可以阻断槟榔碱的心血管作用，具有与东莨菪碱相同的辨别刺激作用，并且在抗抑郁试验中与东莨菪碱一样活跃。即使在大剂量时也不会抑制正在进行的行为，并且它能够竞争性地拮抗槟榔碱的抑制作用，而我们预计东莨菪碱不能做到这一点。在施用大剂量之前，L 687,306 对记忆和注意力的影响很小，因为该药物镇静作用非常小，并且在类似的测定中拮抗东莨菪碱的抗认知作用，体外测定将表明 L 687,306 的结合特征与东莨菪碱的结合特征有何不同。，并在此基础上，将应用化学建模来改进假定的关键区别，通过这个过程，我们预计能够指定毒蕈碱拮抗剂改善抑郁症的受体机制，这些受体机制与导致认知受损的受体机制有何不同，并指定可能具有改善的抗抑郁活性的化学实体。