Early Stage Studies of a Novel Positive Allosteric Modulator of the Alpha1-Adrenergic Receptor to Treat Alzheimer's Disease

新型α1-肾上腺素受体正变构调节剂治疗阿尔茨海默病的早期研究

• 批准号: 10609481
• 负责人: DIANNE M PEREZ
• 金额: $ 40.25万
• 依托单位: CLEVELAND CLINIC LERNER COM-CWRU
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-05-15 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10609481
• 关键词: 3-Dimensional; 3xTg-AD mouse; Adrenergic Receptor; Affect; Affinity; Agonist; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease patient; Amyloid; Amyloid beta-Protein; Animal Model; Animals; Antibodies; Apoptotic; Area; Behavior; Binding; Biodistribution; Biological; Biological Assay; Biological Availability; Blinded; Blood Pressure; Brain; Calcium; Cardiac; Characteristics; Chemicals; Chronic; Clinical Trials; Cognition; Cognitive; Cyclic AMP; Data Analyses; Derivation procedure; Disease; Distant; Dose; Drug Industry; Epinephrine; G-Protein-Coupled Receptors; Grant; Hippocampus; Hormones; Imaging technology; Immunotherapy; Impaired cognition; In Situ; In Vitro; Inositol Phosphates; Knockout Mice; Laboratories; Lead; Learning; Ligands; Light; Long-Term Potentiation; Longevity; Marketing; Measures; Mediating; Memory; Methods; Modeling; Molecular; Molecular Conformation; Molecular Weight; Mus; Mutation; Natural regeneration; Nerve Degeneration; Neurofibrillary Tangles; Norepinephrine; Oral; Penetrance; Peripheral; Pharmaceutical Preparations; Pharmacologic Substance; Pharmacology; Phenotype; Play; Property; Publishing; Rapid screening; Rattus; Receptor Activation; Reflux; Reporting; Research; Rodent Model; Role; Senile Plaques; Signal Transduction; Site; Structure; Synapses; Synaptic plasticity; System; Therapeutic; Time; Toxic effect; Transgenic Animals; Transgenic Mice; adult neurogenesis; aged; analog; animal model development; antagonist; beta-Galactosidase; blood pressure elevation; cardiovascular effects; cognitive benefits; cognitive enhancement; cognitive function; density; drug development; efficacy study; fluorescence imaging; follow-up; improved; in vivo; innovation; mouse model; neurogenesis; neuron loss; neuroprotection; neurotransmission; novel; novel drug class; novel strategies; novel therapeutics; overexpression; positive allosteric modulator; radiotracer; receptor; receptor binding; response; side effect; synaptic function; targeted agent; tau Proteins; vasoconstriction

Approximately 30% of the drugs on the market exert their biological activities upon binding to G-protein Coupled Receptors (GPCRs). As biological targets, GPCRs are associated with exceptional progress in the field of drug research, enabling the application of molecular strategies for the discovery of innovative therapeutic principles. However, a short coming of this class of drugs that bind to the orthosteric site allows for many potential adverse side effects by also targeting other closely related receptor subtypes and other off- target sits. A new class of drugs called allosteric modulators are rapidly being developed in the pharmaceutical industry that limit these shortcomings by binding to unique sites on the receptor separate from the orthosteric site and have no activity on their own. Positive allosteric modulators (PAMs) enhance endogenous ligand activity through either augmenting efficacy or potency and only when the endogenous ligand is bound to the receptor. So an “off” receptor stays off even if the PAM is circulating in the body. While Alzheimer’s Disease (AD) is characterized by neuritic plaques and neurofibrillary tangles, composed mostly of b-amyloid and tau, clinical trials focused on amyloid immunotherapies have been disappointing. Loss of neuronal synaptic density is another invariant feature of the disease that appears to precede neuronal loss and this is where agents targeted to enhance neurogenesis, long term potentiation, and synaptic plasticity in cognitive areas may benefit AD patients and may provide an alternative method of treatment, particularly in light of the disappointing immunotherapies. The α1A-adrenergic receptor (AR) subtype is a GPCR together with two-other closely related subtypes (a1B, a1D) plus six other more distantly-related subtypes (b1, b2, b3, a2A, a2B, a2C). We have previously shown in vivo and in vitro that the α1A-AR subtype is expressed in key cognitive centers of the brain, is both cardiac and neuroprotective, and activation of this receptor can increase cognition, synaptic plasticity, long term potentiation, and adult neurogenesis in normal WT mice. We have developed a novel small molecular weight compound that is orally bioactive and is a PAM of the a1A-AR. It is selective for the norepinephrine-bound receptor only and has no effect on the epinephrine-bound receptor. This PAM is not an agonist and does not invoke signaling on its own. However, it potentiates the NE-mediated cAMP response which is responsible for the cognitive benefits of NE in the brain with no effects on the inositol phosphate response which mediates peripheral cardiovascular effects, and particularly increased blood pressure. We have performed a 10 month dosing study with this PAM in vivo in the 3xTG AD mouse model and showed statistically increased long term potentiation, synaptic plasticity, and cognitive improvement with no apparent toxicity and no increase in blood pressure. Our objective is to further derivatize our lead PAM to improve its novel features, to perform target engagement studies, and to show dose-efficacy in an aged normal rat model.

市场上大约30%的药物在与G蛋白结合后发挥其生物活性 偶联受体（GPCR）。作为生物学靶标，GPCR与生物学领域的异常进展相关。 药物研究领域，使分子策略的应用，发现创新的治疗原则。然而，结合到正构位点的这类药物的短缺还通过靶向其他密切相关的受体亚型和其他脱靶位点而允许许多潜在的不良副作用。在制药工业中正在迅速开发一类称为变构调节剂的新药，其通过结合到受体上与正构位点分开的独特位点来限制这些缺点，并且自身没有活性。正变构调节剂（PAM）通过增强功效或效力并且仅当内源性配体与受体结合时增强内源性配体活性。因此，即使PAM在体内循环，“关闭”受体也会保持关闭状态。虽然阿尔茨海默病（AD）的特征在于主要由b-淀粉样蛋白和tau蛋白组成的神经炎性斑块和神经纤维缠结，但专注于淀粉样蛋白免疫疗法的临床试验一直令人失望。神经元突触密度的丧失是该疾病的另一个不变特征，其似乎先于神经元丧失，并且这是其中靶向增强认知区域中的神经发生、长时程增强和突触可塑性的药剂可使AD患者受益并且可提供替代治疗方法，特别是鉴于令人失望的免疫疗法。α 1A-肾上腺素能受体（AR）亚型是一种GPCR，与其他两种密切相关的亚型（a1 B，a1 D）以及其他六种更远距离相关的亚型（b1，b2，b3，a2 A，a2 B，a2 C）一起。我们之前在体内和体外研究中已经表明，α1A-AR亚型在大脑的关键认知中心表达，具有心脏和神经保护作用，并且该受体的激活可以增加正常WT小鼠的认知、突触可塑性、长时程增强和成年神经发生。我们开发了一种新的小分子量 所述化合物具有口腔生物活性并且是a1 A-AR的PAM。它对去甲肾上腺素结合的 受体，对肾上腺素结合受体没有影响。这种PAM不是激动剂，本身不引发信号传导。然而，它增强NE介导的cAMP反应，这是NE在脑中的认知益处的原因，而对磷酸肌醇反应没有影响，磷酸肌醇反应介导外周心血管作用，特别是血压升高。我们已经在3xTG AD小鼠模型中用该PAM进行了10个月的体内给药研究，并且显示了统计学上增加的长时程增强、突触可塑性和认知改善，而没有明显的毒性并且没有血压升高。我们的目标是进一步衍生化我们的领先PAM，以改善其新的功能，进行目标接合研究，并显示在老年正常大鼠模型的剂量-疗效。