New Classes of AChE Inhibitors with Additional Pharmacological Effects of Interest for the Treatment of Alzheimer's Disease
by
Villarroya M, Garcia AG, Marco JL.
Instituto "Teofilo Hernando",
Departamento de Farmacologia y Terapeutica,
Facultad de Medicina,
Universidad Autonoma de Madrid,
28029-Madrid, Spain.
mercedes.villarroya@uam.es.
Curr Pharm Des. 2004;10(25):3177-84

ABSTRACT

Alzheimer's disease (AD) is associated to a gradual loss of attention and memory that have been associated to impairment of brain cholinergic neurotransmission, particularly a deficit of cholinergic neurons in the nucleus basalis of Meynert. Thus, it is not surprising that the first therapeutic target that has demonstrated therapeutic efficacy on cognition, behaviour and functional daily activities has been the inhibitors of acetylcholinesterase (AChE), i.e. tacrine, donepezil, rivastigmine and galanthamine. But not all inhibitors of AChE have the same potency to block the enzyme and have a different pharmacological profile. For instance, rivastigmine is a dual inhibitor of AChE and butyrylcholinesterase (BuChE), and galanthamine is a mild inhibitor of AChE and an allosteric potentiating ligand of neuronal nicotinic receptors for acetylcholine (nAChRs). In addition, we have recently found that galanthamine has neuroprotective effects by inducing calcium signals and the induction of the antiapoptotic protein Bcl-2. In this frame, we have been synthesizing new tacrine derivatives that keep their ability to inhibit AChE but that interfere with neuronal calcium overloading and prevent apoptosis. Some of these compounds exhibit neuroprotecting properties and thus, could be useful in the treatment of neurodegenerative and ischaemic brain diseases.

Tacrine
Rivastigmine
Galantamine
Rivastigmine
Alzheimer's disease
Cholinesterase inhibitors
Cholinergic precursor therapy
Acetylcholine and consciousness
Anti-muscarinics/dumb-drug euphoria

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