ANTI-PCP AGENTS FOR AIDS AND DRUG ABUSE

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，是AIDS患者死亡的主要原因。艾滋病毒/艾滋病患者和兴奋剂滥用史可能特别容易受到神经毒性导致认知障碍。例如，艾滋病痴呆和滥用精神兴奋剂（如安非他明和可卡因）与神经毒性有关，可能是由N-甲基-D-天冬氨酸（NMDA）受体系统激活引起的。喷他脒是广泛用于治疗艾滋病相关PCP的首选药物之一。最近，这种药物被证明是一种有效的NMDA受体拮抗剂，具有神经保护作用。然而，该药物与限制其使用的毒副作用的高发生率相关。因此，迫切需要具有限制其使用的作用的更有效且毒性更小的抗PCR药物。因此，迫切需要具有神经保护作用的更有效和毒性更低的抗PCP药物来治疗这一滥用兴奋剂的AIDS患者群体。喷他脒是一种柔性分子，可以呈现许多相互转化的构象。其作用的分子机制尚不清楚。我们推测，戊烷脒的构象灵活性允许结合不同的大分子，这可能至少部分地解释了药物的治疗作用和毒性作用。我们的目标是通过构象-生物活性关系研究将喷他脒的治疗作用与其毒性作用分开。为了验证这一假设，我们建议进行以下研究：a）设计并合成与喷他脒相关的构象限制性类似物; B）确定其物理化学性质c）在卡氏肺孢子虫培养模型中评价合成化合物的体外抗PCR活性; d）在疾病的动物模型中评价最有希望的化合物的体内抗PCR活性和毒性; f）通过热变性和质谱技术在分子水平上研究所提出的戊烷脒类似物与DNA的相互作用。所获得的信息不仅在确定喷他脒类似物的作用机制方面有价值，而且还可能导致开发具有神经保护作用的更有效和更安全的抗PCR剂。

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.