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

市场上约30%的药物通过与G蛋白结合而发挥其生物活性 偶联受体(GPCRs)。作为生物靶标，GPCRs与在 在药物研究领域，能够应用分子策略来发现创新的治疗原理。然而，这类结合到正位位置的药物的缺点是允许许多潜在的副作用，因为它还针对其他密切相关的受体亚型和其他靶点外的位置。一种名为变构调节剂的新型药物正在制药行业迅速开发，它们通过与受体上与正构化位点分离的独特位点结合来限制这些缺点，并且本身没有任何活性。正变构调节剂(PAM)只有在内源性配体与受体结合的情况下，才能通过增强疗效或效力来增强内源性配体的活性。因此，即使PAM在体内循环，“OFF”受体也不会出现。虽然阿尔茨海默病(AD)的特点是神经性斑块和神经原纤维缠结，主要由b-淀粉样蛋白和tau组成，但专注于淀粉样蛋白免疫治疗的临床试验一直令人失望。神经元突触密度的丢失是该疾病的另一个不变特征，似乎先于神经元丢失，这就是靶向增强认知区域的神经发生、长时程增强和突触可塑性的药物可能使AD患者受益，并可能提供另一种治疗方法，特别是在免疫疗法令人失望的情况下。α1A-肾上腺素能受体(AR)亚型是一个GPCR型，它与其他两个亲缘关系密切的亚型(a1B，a1D)以及另外六个亲缘关系较远的亚型(b1，b2，b3，a2a，a2b，a2c)结合在一起。我们以前在体内和体外已经证明，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，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。我们已经开发出一种新型的小分子量 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有选择性。 仅作用于受体，对肾上腺素结合受体无影响。这种PAM不是一种激动剂，也不会自行激活信号。然而，它增强了NE介导的cAMP反应，而NE对大脑中NE的认知益处负责，而对介导外周心血管效应的肌醇磷酸反应没有影响，特别是血压升高。我们在3xTg AD小鼠模型中进行了10个月的体内剂量研究，结果显示长时程增强、突触可塑性和认知改善都有统计学意义的增加，没有明显的毒性和血压升高。我们的目标是进一步衍生化我们的铅PAM，以改进其新特性，进行靶向参与研究，并在老年正常大鼠模型中显示剂量效应。

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.