Department of Pharmaceutical Sciences, College of Pharmacy, Northeast Ohio Medical University, Rootstown, Ohio, USA.
Int Rev Neurobiol. 2011;100:107-25. doi: 10.1016/B978-0-12-386467-3.00006-6.
This chapter discusses the rationale for developing multimodal or multifunctional drugs (also called designed multiple ligands or DMLs) aimed at disease-modifying treatment strategies for the most common neurodegenerative diseases Alzheimer's and Parkinson's disease (AD and PD). Both the prevalence and incidence of AD and PD have seen consistent and dramatic increases, a disconcerting phenomenon which, ironically, has been attributed to extended life expectancy brought about by better health care globally. In spite of these statistics, the development and introduction to the clinic of new therapies proven to prevent or delay the onset of AD and PD have been disappointing. Evidence has accumulated to suggest that the etiopathology of these diseases is extremely complex, with an array of potential drug targets located within a number of deleterious biochemical pathways. Therefore, in these diseases, it is unlikely that the complex pathoetiological cascade leading to disease initiation or progression will be mitigated by any one drug acting on a single pathway or target. The pursuit of novel DMLs may offer far better outcomes. Although certainly not the only, and perhaps not even the best, approach but farthest along the drug development pipeline in the DML paradigm are drugs that combine inhibition of monoamine oxidase with associated etiological targets unique to either AD or PD. These compounds will constitute the major focus of this chapter, which will also explore radically new paradigms that seek to combine cognitive enhancers with proneurogenesis compounds.
这一章讨论了开发多模式或多功能药物（也称为设计的多重配体或 DML）的基本原理，这些药物旨在针对最常见的神经退行性疾病阿尔茨海默病和帕金森病（AD 和 PD）制定疾病修正治疗策略。AD 和 PD 的患病率和发病率都持续且显著增加，这一令人不安的现象具有讽刺意味的是，这归因于全球更好的医疗保健带来的预期寿命延长。尽管有这些统计数据，但已证明可预防或延迟 AD 和 PD 发作的新疗法的开发和引入临床一直令人失望。有证据表明，这些疾病的病因病理学极其复杂，许多潜在的药物靶点位于许多有害的生化途径内。因此，在这些疾病中，不太可能通过作用于单一途径或靶点的任何一种药物来减轻导致疾病发生或进展的复杂病理生理级联反应。探索新型 DML 可能会带来更好的结果。尽管 DML 范式中的药物开发管道中已经有了一些进展，但这肯定不是唯一的方法，甚至可能不是最好的方法，但这些药物将组合单胺氧化酶抑制与 AD 或 PD 特有的相关病因靶点结合使用。这些化合物将构成本章的主要重点，还将探讨寻求将认知增强剂与神经发生化合物结合的全新范例。
