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: 10380631
• 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/10380631
• 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; 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; antagonist; base; 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; 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.

市场上大约30%的药物通过与g蛋白结合发挥其生物活性