Preclinical Identification of Better Antimuscarinic Antidepressants

 描述(申请人提供)：最近有报道称东莨菪碱在人类中具有抗抑郁作用，这让人们产生了希望，即这种抗心肌梗死药物代表着对血清素和去甲肾上腺素能再摄取阻滞剂的改进，这两种药物几十年来一直是抗抑郁药物的基础。东莨菪碱的作用起效迅速，持续时间相当长，与以前的药物相比有相当大的优势。令人担忧的是，东莨菪碱在治疗抑郁症方面被广泛用于人类和动物研究，以模拟认知障碍和痴呆症。因此，东莨菪碱的抗抑郁作用有可能与该药物众所周知的对注意力、学习和记忆的有害影响并存。当前提议所基于的假设是，这两种影响可以分开。例如，它们可能由不同的受体亚型或这些受体的不同效力所介导。我们的计划是对一系列选定的抗霉菌药物进行评估 协调分析，旨在了解他们的活动概况。化验将从体内评估开始，以确定一种药物是否为中枢和外周的毒扁豆碱拮抗剂。因此，将描述其在抗抑郁剂以及学习和记忆测试中的作用，如果产生抗抑郁药样作用所需的剂量明显小于干扰认知能力所需的剂量，则将测量其在五种M受体亚型上的亲和力和有效性。这将决定是否是一个或多个受体亚型的选择性赋予了抗抑郁作用，同时减少了抗认知作用。将对候选化合物进行化学建模，试图改善它们的活性光谱，以便在预期和非靶标效应之间有更大的药理学差异。从我们的先导化合物L687,306获得的数据鼓励我们努力追求这一目标。根据文献，L 687,306是M2和M3拮抗剂，对M1受体的作用非常轻微，在认知测试中能够改善东莨菪碱的作用。在我们的测试中，它阻断槟榔碱的心血管效应，具有与东莨菪碱相同的区别性刺激作用，在抗抑郁测试中与东莨菪碱一样有效。它与东莨菪碱的不同之处在于，即使在大剂量下，它也不能抑制正在进行的行为，而且它能够竞争性地拮抗槟榔碱的抑制作用，而东莨菪碱不能做到这一点。我们预计，在大剂量给药之前，L 687,306对记忆和注意力的影响不大，因为该药几乎没有镇静作用，并在类似的实验中拮抗东莨菪碱的抗认知作用。体外试验将显示L 687,306的结合谱与东莨菪碱的结合谱有何不同，在此基础上，将应用化学模拟来改进假定的临界区分。通过这一过程，我们预计能够指定毒扁豆碱拮抗剂改善抑郁的受体机制，这些机制与导致认知障碍的受体机制有何不同，并指定可能具有改善抗抑郁活性的化学实体。

 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.