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%的药物通过与G蛋白结合发挥其生物活性 偶联受体 (GPCR) 作为生物靶标，GPCR 与化学领域的特殊进展相关。 然而，此类与正位点结合的药物的缺点是，由于还针对其他密切相关的受体亚型，因此会产生许多潜在的不良副作用。制药行业正在迅速开发一类称为变构调节剂的新型药物，它通过与受体上与正构位点分开的独特位点结合来限制这些缺点，并且其本身没有正向变构活性。调节剂 (PAM) 通过增强功效或效力来增强内源性配体活性，并且仅当内源性配体与受体结合时，即使 PAM 在体内循环，“关闭”受体也会保持关闭状态。其特点是神经炎斑块和神经原纤维缠结，主要由 β 淀粉样蛋白和 tau 蛋白组成，针对淀粉样蛋白免疫疗法的临床试验令人失望。密度是该疾病的另一个不变特征，似乎先于神经元损失，这就是针对增强认知区域神经发生、长期增强和突触可塑性的药物可能使 AD 患者受益，并可能提供替代治疗方法，特别是在光密度方面。 α1A-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（a1B、a1D）以及其他六种关系较远的亚型一起。 （b1、b2、b3、a2A、a2B、a2C）我们之前已经在体内和体外证明，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，并且可以激活该受体。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。 具有口服生物活性的化合物，是 a1A-AR 的 PAM，它对去甲肾上腺素结合具有选择性。 该 PAM 只作用于肾上腺素受体，对肾上腺素结合受体没有影响，它本身不会引发信号传导，但它会增强 NE 介导的 cAMP 反应，从而增强 NE 在大脑中的认知作用。对介导外周心血管效应的磷酸肌醇反应没有影响，尤其是血压升高。我们在 3xTG AD 小鼠模型中进行了一项为期 10 个月的体内给药研究，结果显示长期显着增加。我们的目标是进一步衍生我们的先导 PAM，以改善其新功能，进行目标参与研究，并在老年正常人中显示剂量疗效。大鼠模型。