ANTI-PCP AGENTS FOR AIDS AND DRUG ABUSE

用于治疗艾滋病和药物滥用的抗五氯苯酚药物

• 批准号: 6318326
• 负责人: TIEN L HUANG
• 金额: $ 5.71万
• 依托单位: XAVIER UNIVERSITY OF LOUISIANA
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-06-01 至 2001-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6318326
• 关键词: AIDS therapy; NMDA receptors; Pneumocystis pneumonia; analog; chemical structure function; conformation; disease /disorder model; drug addiction antagonist; drug design /synthesis /production; drug screening /evaluation; laboratory rat; mass spectrometry; microorganism disease chemotherapy; neuropharmacology; neuroprotectants; pentamidine; tissue /cell culture

Pneumocystis carinii pneumonia (PCP)_ is the most common serious opportunistic infection in patients with acquired immunodeficiency syndrome (AIDS) and is a major cause of mortality in these patients. Patients with HIV/AIDS and a history of stimulant abuse may be particularly vulnerable to neurotoxicity leading to cognitive impairment. For instance, AIDS dementia and a abuse of psychostimulants (e.g. amphetamines and cocaine) are associated with neurotoxicity presumably caused by activation of the N-methyl-D-aspartate (NMDA) receptors systems. Pentamidine is one of the drugs of choice used extensively for the treatment of AIDS-related PCP. Recently, this drug was shown to be potent NMDA receptor antagonist with neuroprotective properties. However, the drug is associated with a high incidence of toxic side effects which limits its use. There is therefore, a critical need for more potent and less toxic anti- PCR drugs with effects which limits its use. There is therefore, a critical need for more potent and less toxic anti-PCP drugs with neuroprotective effects for treating this population of stimulant-abusing AIDS patients. Pentamidine is a flexible molecule and can assume a number of interconvertible conformations. Its molecular mechanism(s) of action is (re unclear. We hypothesize that the conformational flexibility of pentamidine allows to bind to different macromolecules and this may account at least in part, for the therapeutic as well as toxic actions of the drug. Our goal is to separate the therapeutic actions of pentamidine from its toxic actions via conformation-biological activity relationship studies. To test this hypothesis, we propose to conduct the following studies: a) design and synthesize conformational restricted analogues related to pentamidine; b) determine the physicochemical properties (pKa and log P) of the synthesized compounds; c) evaluate the in vitro anti-PCR activity of the synthesized compounds in a P. carinii cultured model; d) evaluate the in vivo anti-PCR activity and toxicity of the most promising compounds in an animal model of the disease; e) evaluate the in vitro NMDA receptor antagonist activity and neuroprotective effects of the synthesized compounds; f) study the interactions of the proposed pentamidine analogues with DNA t the molecular level via thermal denaturation and mass spectrometry techniques. The information gained will be valuable not only in determining the mechanism(s) of action of the pentamidine analogues, but may also result in the development of a more effective and safer anti-PCR agent with neuroprotective actions.

卡氏肺孢子虫肺炎(PCP)是获得性免疫缺陷综合征(AIDS)患者最常见的严重机会性感染，也是导致这些患者死亡的主要原因。有兴奋剂滥用史的艾滋病毒/艾滋病患者可能特别容易受到神经毒性的影响，从而导致认知障碍。例如，艾滋病、痴呆症和滥用精神刺激剂(如安非他明和可卡因)可能与N-甲基-D-天冬氨酸(NMDA)受体系统激活引起的神经毒性有关。扑热息痛是广泛用于治疗艾滋病相关PCP的首选药物之一。最近，该药被证明是一种具有神经保护作用的NMDA受体拮抗剂。然而，这种药物与毒副作用的高发生率有关，这限制了它的使用。因此，迫切需要更有效和毒性更低的抗聚合酶链式反应药物，其效果限制了它的使用。因此，迫切需要更有效、毒性更低、具有神经保护作用的抗PCP药物来治疗这类滥用兴奋剂的艾滋病患者。五烷双胺是一种灵活的分子，可以呈现多种可相互转化的构象。其作用的分子机制(S)尚不清楚。我们假设，五烷双胺的构象灵活性允许与不同的大分子结合，这可能至少部分解释了该药物的治疗和毒性作用。我们的目标是通过构象-生物活性关系研究来分离五烷双胺的治疗作用和毒性作用。为了验证这一假说，我们提议进行以下研究：a)设计并合成与卡氏肺孢子虫相关的构象受限类似物；b)测定合成化合物的物理化学性质(pKA和logP)；c)在卡氏肺孢子虫培养模型中评估合成化合物的体外抗PCR活性；d)在动物模型中评估最有希望的化合物的抗PCR活性和毒性；e)评估合成化合物的体外NMDA受体拮抗剂活性和神经保护作用；f)通过热变性和质谱分析技术从分子水平研究拟议的戊二胺类似物与DNA的相互作用。所获得的信息不仅对确定戊双胺类似物的作用机制(S)有价值，而且可能导致开发一种更有效、更安全的具有神经保护作用的抗聚合酶链式反应药物。