Acetylcholinesterase Noncovalent Inhibitors Based on a Polyamine Backbone for Potential Use against Alzheimer's Disease

• Published in: Journal of medicinal chemistry 1998-10, Vol.41 (22), p.4186-4189
• Main Authors: Melchiorre, Carlo, Andrisano, Vincenza, Bolognesi, Maria L, Budriesi, Roberta, Cavalli, Andrea, Cavrini, Vanni, Rosini, Michela, Tumiatti, Vincenzo, Recanatini, Maurizio
• Format: Article
• Language: English
• Subjects: Acetylcholinesterase - metabolism; Alzheimer Disease - drug therapy; Binding Sites; Biological and medical sciences; Butyrylcholinesterase - metabolism; Cholinergic system; Cholinesterase Inhibitors - chemistry; Cholinesterase Inhibitors - metabolism; Cholinesterase Inhibitors - pharmacology; Erythrocytes - enzymology; Humans; Kinetics; Ligands; Medical sciences; Models, Molecular; Neuropharmacology; Neurotransmitters. Neurotransmission. Receptors; Pharmacology. Drug treatments; Polyamines - chemistry; Polyamines - metabolism; Polyamines - pharmacology; Receptor, Muscarinic M2; Receptors, Muscarinic - metabolism; Structure-Activity Relationship
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm9810452

Dementia is the most common psychiatric disorder in elderly patients, and Alzheimer's disease (AD) is the most common cause. Much effort is devoted to elucidating the relationships among the hallmarks of the disease: amyloid plaques, neurofibrillary tangles, and degeneration of the basal forebrain cholinergic neurons. Despite the evidence that there is a profound and consistent loss of cholinergic transmission in AD, pharmacotherapy and practical medicine are still waiting for the possible advantages arising from enhancing the cholinergic system in some way. To date, only some inhibitors of acetylcholinesterase (AChE), such as tacrine and donepezil, resulted to be useful drugs in alleviating the symptoms of AD. On the other hand, the existence of multiple muscarinic receptor subtypes in the central nervous system (CNS) has stimulated the search for new drugs which target only one receptor while not affecting others. It has been advanced that drugs which antagonize selectively presynaptic muscarinic M sub(2) autoreceptors may also be useful in AD as they will facilitate ACh release. AChE is the enzyme involved in the hydrolysis of the neurotransmitter acetylcholine (ACh) at cholinergic synapses in the central and peripheral nervous systems. Inhibitors of AChE activity promote an increase in the concentration and the duration of action of synaptic ACh thus causing an enhancement of the cholinergic transmission through the activation of the synaptic nicotinic and muscarinic receptors. It has been demonstrated that AChE could play a key role during an early step in the development of the senile plaques, as revealed by the finding that AChE accelerates beta -amyloid peptide ( beta A) deposition. This peculiar feature of AChE was not affected by active site inhibitors, such as edrophonium, but it was affected by peripheral anionic binding site ligands, such as decamethonium and propidium. Interestingly enough, butyrylcholinesterase (BChE), an enzyme that lacks the peripheral anionic binding site, did not affect amyloid formation. This finding suggests clearly that the catalytic site of AChE does not participate in the interaction of the enzyme with beta A, whereas it is possible that the peripheral binding site of AChE may be involved in amyloid formation.