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: 10153647
• 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/10153647
• 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; Bioavailable; Biodistribution; Biological; Biological Assay; Blinded; Blood Pressure; Brain; Calcium; Cardiac; Characteristics; Chemicals; Chronic; Clinical Trials; Cognition; Cognitive; Cyclic AMP; Data Analyses; Disease; Distant; Dose; Drug Industry; Epinephrine; G-Protein-Coupled Receptors; GTP-Binding Protein alpha Subunits, Gs; Galactosidase; Grant; Hippocampus (Brain); Hormones; Imaging technology; Immunotherapy; Impaired cognition; In Situ; In Vitro; Inositol Phosphates; Knockout Mice; Laboratories; Lead; Learning; Ligands; Light; Long-Term Potentiation; Longevity; 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; base; 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; neurotransmission; novel; novel drug class; novel strategies; novel therapeutics; 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.

市场上约有30％的药物在与G蛋白结合后发挥其生物学活性 耦合受体（GPCR）。作为生物学靶标，GPCR与在 药物研究领域，使分子策略在发现创新的治疗原理中的应用。但是，这类与直角位点结合的药物的短暂降临可以通过靶向其他密切相关的受体亚型和其他非靶位点来产生许多潜在的不良副作用。在制药行业中，正在迅速开发一种称为变构调节剂的新药物，该药物通过与直角部位分开的独特位点结合而限制了这些缺陷，并且没有自己的活动。阳性变构调节剂（PAM）通过提高效率或效力来增强内源配体活性，并且仅当内源配体与受体结合时。因此，即使PAM在体内循环，“ OFF”受体仍会落后。尽管阿尔茨海默氏病（AD）的特征是神经质斑块和神经原纤维缠结，主要由B-淀粉样蛋白和TAU组成，但针对淀粉样蛋白免疫治疗的临床试验令人失望。神经元突触密度的丧失是该疾病的另一个不变特征，似乎是在神经元丧失之前的，这是针对增强神经发生，长期潜力和认知区域的合成可塑性的靶向代理，鉴于令人失望的免疫治疗症，可能会使AD患者受益。 α1A-肾上腺素能受体（AR）亚型是GPCR，以及两个又有两个密切相关的亚型（A1B，A1D），再加上另外六个更遥远的亚型（B1，B1，B2，B3，A2A，A2A，A2B，A2B，A2C）。我们先前在体内和体外已经表明，α1A-AR亚型在大脑的关键认知中心表达，既是心脏和神经保护剂，并且该受体的激活可以增加正常WT小鼠中的认知，突触可塑性，长期增强性，长期增强和成人神经发生。我们已经开发了一种新颖的小分子量 口服生物活性的化合物，是A1A-AR的PAM。它是针对去甲肾上腺素的选择性的 仅受体，对肾上腺素结合的受体没有影响。这种PAM不是激动剂，也不是单独调用信号。然而，它可能会导致NE介导的cAMP反应，该反应导致NE在大脑中的认知益处，而对介导外周心血管效应的肌醇磷酸盐反应没有影响，尤其是增加了血压。我们在3xtg AD小鼠模型中使用该PAM在体内进行了10个月的给药研究，并显示出统计学上增加的长期增强，突触可塑性和认知改善，没有明显的毒性且没有血压升高。我们的目标是进一步衍生我们的铅PAM，以改善其新型特征，进行目标参与研究并显示老年正常大鼠模型中的剂量效应。