Department of Medicine (Neurology and Geriatric Medicine), Dalhousie University, 5850 College Street, Halifax, Nova Scotia, Canada B3H 4R2.
Bioorg Med Chem Lett. 2013 Jul 1;23(13):3822-5. doi: 10.1016/j.bmcl.2013.04.082. Epub 2013 May 7.
Synthetic derivatives of phenothiazine have been used for over a century as well-tolerated drugs against a variety of human ailments from psychosis to cancer. This implies a considerable diversity in the mechanisms of action produced by structural changes to the phenothiazine scaffold. For example, chlorpromazine treatment of psychosis is related to its interaction with dopaminergic receptors. On the other hand, antagonistic action of such drugs on cholinergic receptor systems would be counter-productive for treatment of Alzheimer's disease. In a search for phenothiazines that are inhibitors of cholinesterases, especially butyrylcholinesterase, with potential to treat Alzheimer's disease, we wished to ascertain that such molecules could be devoid of neurotransmitter receptor interactions. To that end, a number of our synthetic N-10-carbonyl phenothiazine derivatives, with cholinesterase inhibitory activity, were tested for interaction with a variety of neurotransmitter receptor systems. We demonstrate that phenothiazines can be prepared without significant neurotransmitter receptor interactions while retaining high potency as cholinesterase ligands for treatment of Alzheimer's disease.
吩噻嗪的合成衍生物作为一种耐受良好的药物，已被使用了一个多世纪，可用于治疗从精神病到癌症等多种人类疾病。这意味着吩噻嗪骨架结构的变化会产生相当多样化的作用机制。例如，氯丙嗪治疗精神病与它与多巴胺能受体的相互作用有关。另一方面，此类药物对胆碱能受体系统的拮抗作用对于治疗阿尔茨海默病来说是适得其反的。为了寻找具有治疗阿尔茨海默病潜力的、可抑制乙酰胆碱酯酶（尤其是丁酰胆碱酯酶）的吩噻嗪类化合物，我们希望确定此类分子可以不与神经递质受体相互作用。为此，我们对具有乙酰胆碱酯酶抑制活性的多种合成 N-10-羰基吩噻嗪衍生物进行了测试，以研究它们与各种神经递质受体系统的相互作用。我们证明，吩噻嗪类化合物可以在不与神经递质受体发生显著相互作用的情况下制备，同时保持作为乙酰胆碱酯酶配体治疗阿尔茨海默病的高活性。
