ANTI-PCP AGENTS FOR AIDS AND DRUG ABUSE

卡氏肺囊虫肺炎（PCP）_是获得性免疫缺陷综合征（艾滋病）患者中最常见的严重机会性感染，也是这些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）受体系统的激活引起的。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，该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，该药的毒副作用发生率高，限制了其使用。因此，迫切需要更有效和毒性更小的抗PCR药物，其作用限制了其使用。因此，迫切需要更有效、毒性更小、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。喷他脒是一种灵活的分子，可以形成多种可相互转换的构象。其作用的分子机制尚不清楚。我们假设喷他脒的构象灵活性允许与不同的大分子结合，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-生物活性关系研究分离喷他脒的治疗作用和毒性作用。为了验证这一假设，我们建议进行以下研究：a)设计和合成与喷他脒相关的构象限制类似物；b)测定合成化合物的理化性质（pKa和log P）；c)评价合成化合物在卡氏假单胞菌培养模型中的体外抗pcr活性；d)在该疾病的动物模型中评估最有希望的化合物的体内抗pcr活性和毒性；e)评价合成化合物的体外NMDA受体拮抗剂活性和神经保护作用；f)通过热变性和质谱技术在分子水平上研究所提出的喷他脒类似物与DNA的相互作用。所获得的信息不仅对确定喷他脒类似物的作用机制有价值，而且可能导致开发更有效和更安全的具有神经保护作用的抗pcr试剂。

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.