Mechanisms mediating the attention-enhancing effects of nicotinic receptor agents

烟碱受体药物增强注意力作用的介导机制

• 批准号: 8649926
• 负责人: Britta Hahn
• 金额: $ 42.79万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-03-15 至 2019-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8649926
• 关键词: Adrenergic Agents; Adrenergic Receptor; Adverse effects; Agonist; Alzheimer' s Disease; Area; Attention; Attention deficit hyperactivity disorder; Behavioral; Brain; Chemosensitization; Chronic; Clinical; Clinical Research; Clinical Trials; Cognition; Cognitive; Cognitive deficits; Development; Disease; Dose; Galantamine; Glutamates; Goals; Health; Human; Knowledge; Lead; Ligands; Mecamylamine; Mediating; Modeling; Mutation; Neurotransmitters; Nicotine; Nicotinic Receptors; Nootropic Agents; Pharmaceutical Preparations; Pharmacological Treatment; Play; Prefrontal Cortex; Property; Propranolol; Rattus; Research; Rodent; Role; Schizophrenia; Series; Staging; System; Testing; Therapeutic; Therapeutic Agents; Therapeutic Effect; Translations; Work; acetylcholine receptor agonist; adrenergic; base; clinical practice; clinically relevant; clinically significant; desensitization; drug development; effective therapy; knowledge of results; neurotransmission; never smoker; noradrenergic; novel; pre-clinical; preclinical study; receptor; receptor expression; research study; success

DESCRIPTION (provided by applicant): Diseases such as schizophrenia and Alzheimer's disease are marked by cognitive deficits for which there are to date no effective treatments. Drugs that activate the nicotinic acetylcholine receptor (nAChR) en- hance cognition, most robustly attentional functions. Non-selective nAChR agonists such as the prototypical agonist nicotine have a broad effects profile that includes unwanted side effects. The development of nAChR agonists selective for subtypes of the nAChR has had limited success in maximizing therapeutic and reducing side effects. The overall goal of the present proposal is to generate the knowledge upon which to base a more targeted development of nAChR agents with clinically significant cognitive-enhancing effects. Previous drug development efforts have focused on agonists of the two most widely expressed nAChR subtypes, reflecting the fact that the specific systems and mechanisms mediating the sought-after effects are largely unknown. This project is aimed at identifying the systems and mechanisms through which nAChR agents enhance attentional functions. Employing analogous human and rodent paradigms that we have shown to be reliably sensitive to the attention-enhancing effects of nicotine, this project consists of a series of mutually informative pharmacological characterization studies in healthy human never-smokers and rats. Aim 1 is to potentiate the attention-enhancing effects of nAChR agonism with Allosteric Poten- tiating Ligands (APLs). Interaction studies with low-dose nicotine (as a model agonist) and galantamine will be conducted in humans and rats, and in rats with novel, more selective APLs. Aim 2 is to evaluate the attention-enhancing properties of ultra low-dose nAChR antagonism, suggested by our previous preclinical findings. Studies in humans and rats with the nAChR antagonist mecamylamine will be accompanied by preclinical experiments employing more selective nAChR antagonists, and followed by pharmacological interaction studies to determine the secondary neurotransmitter system(s) involved. Aim 3 is to determine the secondary system(s) mediating the attention-enhancing properties of nAChR agonists. Following our previous preclinical findings, we will aim at antagonizing the attention-enhancing effects of nicotine in humans with a β-adrenoceptor antagonist. Concurrent preclinical experiments will aim at reversing attentional effects of nicotine with noradrenergic, glutamatergic, GABAergic, glycinergic, and histaminergic antagonists at doses devoid of effects by themselves. The resulting knowledge would enable drug development efforts to focus on nAChR subtypes expressed more selectively on those system(s) that mediate effects on attention. Such agents would have reduced unwanted and potentially larger therapeutic effects. Evaluating benefits of APLs and ultra low-dose antagonism diversifies strategies of nAChR modulation with the aim of producing larger effects. The integration of human and rodent findings will facilitate their translation into clinical practice. Overall, the project is expectedto result in nAChR agents with greater clinical potential.

描述（由适用提供）：精神分裂症和阿尔茨海默氏病等疾病的标志是迄今为止没有有效治疗的认知缺陷。激活烟碱乙酰胆碱受体（NACHR）的认知的药物，最强大的注意力功能。非选择性的NACHR激动剂（例如典型的激动剂尼古丁）具有广泛的效果，包括不必要的副作用。 NACHR激动剂对NACHR亚型的发展的发展在最大化治疗和减少副作用方面取得了有限的成功。本提案的总体目标是产生知识，以使NACHR剂具有更有针对性的发展具有临床认知增强作用的知识。先前的药物开发工作集中在两个最广泛表达的NACHR亚型的激动剂上，这反映了以下事实：介导感官后影响的特定系统和机制在很大程度上是未知的。该项目旨在确定NACHR代理增强注意力功能的系统和机制。该项目采用类似的人类和啮齿动物范式对尼古丁的注意力增强作用的可靠敏感，该项目由一系列相互信息的药物表征研究组成，对健康的人类永不吸烟者和大鼠。目的1是通过变构型配体（APLS）增强NACHR激动剂的注意力增强作用。低剂量尼古丁（作为模型激动剂）和甘氨酸的相互作用研究将在人类和大鼠以及具有新颖，更具选择性的大鼠中进行。 AIM 2是评估我们以前的临床前发现提出的超剂量NACHR拮抗作用的注意力增强特性。通过NACHR拮抗剂梅卡米胺在人类和大鼠中进行的研究将伴随着采用更具选择性NACHR拮抗剂的临床前实验，然后进行药物相互作用研究，以确定涉及的二级神经递质系统。 AIM 3是确定介导NACHR激动剂的注意力增强特性的二级系统。遵循我们以前的临床前发现，我们将旨在拮抗具有β-肾上腺素受体拮抗剂的人类尼古丁的注意力增强作用。并发的临床前实验将旨在逆转尼古丁的注意力影响，甲腺能，谷氨酸能，Gabaergic，Gabaergic，Glycinagric和Hentaginagic拮抗剂，其剂量以其自身的作用。由此产生的知识将使药物开发工作能够专注于NACHR亚型，该亚型在那些介导对注意力影响的系统上更有选择性地表达。这样的药物会降低不需要的和潜在的更大的治疗作用。评估APL的益处和超剂量拮抗作用使NACHR调制的策略多样化，目的是产生更大的影响。人类和啮齿动物发现的整合将有助于将其转化为临床实践。总体而言，该项目有望导致NACHR药物具有更大的临床潜力。