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

Journal of Medicinal Chemistry
1998.0

Abstract

Alzheimer's disease (AD) is the leading cause of dementia in elderly patients, associated with cholinergic system degeneration. While acetylcholinesterase (AChE) inhibitors like tacrine and donepezil alleviate symptoms by enhancing cholinergic transmission, AChE also accelerates β-amyloid peptide (βA) aggregation via its peripheral anionic binding site. Additionally, antagonists of presynaptic muscarinic M2 autoreceptors may enhance ACh release. This study aimed to develop novel polyamine backbone ligands with affinity for both AChE active/peripheral sites and M2 receptors to potentiate cholinergic transmission, facilitate ACh release, and inhibit βA aggregation. Starting from benextramine (a tetraamine disulfide with M2 affinity and reversible AChE inhibition), we synthesized and evaluated derivatives (e.g., replacing disulfide with methylenes, modifying chain length or substituents). The most promising compound, caproctamine (9), was a potent AChE inhibitor (Ki = 0.104 μM, ~42-fold more potent than benextramine) with mixed-type inhibition (binding both AChE sites, confirmed by kinetic studies and molecular docking). It also displayed affinity for M2 receptors (pA2 = 6.39) and low butyrylcholinesterase (BChE) selectivity. Conclusion: Caproctamine has a balanced profile to stimulate cholinergic activity and potentially inhibit βA aggregation, making it a promising candidate for AD research, though blood-brain barrier penetration requires further validation.

Knowledge Graph

Similar Paper

Acetylcholinesterase Noncovalent Inhibitors Based on a Polyamine Backbone for Potential Use against Alzheimer's Disease
Journal of Medicinal Chemistry 1998.0
Biosynthesis of the lincomycins. 1. Studies using stable isotopes on the biosynthesis of the propyl- and ethyl-L-hygric acid moieties of lincomycins A and B
Journal of the American Chemical Society 1984.0
Structure−Activity Relationships of Acetylcholinesterase Noncovalent Inhibitors Based on a Polyamine Backbone. 3. Effect of Replacing the Inner Polymethylene Chain with Cyclic Moieties
Journal of Medicinal Chemistry 2004.0
Structure−Activity Relationships of Acetylcholinesterase Noncovalent Inhibitors Based on a Polyamine Backbone. 2. Role of the Substituents on the Phenyl Ring and Nitrogen Atoms of Caproctamine
Journal of Medicinal Chemistry 2003.0
Structure−Activity Relationships of Acetylcholinesterase Noncovalent Inhibitors Based on a Polyamine Backbone. 4. Further Investigation on the Inner Spacer
Journal of Medicinal Chemistry 2008.0
Design, synthesis, and bioevaluation of benzamides: Novel acetylcholinesterase inhibitors with multi-functions on butylcholinesterase, Aβ aggregation, and β-secretase
Bioorganic & Medicinal Chemistry 2012.0
Benzophenone-based derivatives: A novel series of potent and selective dual inhibitors of acetylcholinesterase and acetylcholinesterase-induced beta-amyloid aggregation
European Journal of Medicinal Chemistry 2011.0
Synthesis, biological evaluation and molecular modeling of new tetrahydroacridine derivatives as potential multifunctional agents for the treatment of Alzheimer’s disease
Bioorganic & Medicinal Chemistry 2015.0
Design, synthesis and evaluation of phthalide alkyl tertiary amine derivatives as promising acetylcholinesterase inhibitors with high potency and selectivity against Alzheimer's disease
Bioorganic & Medicinal Chemistry 2020.0
Propidium-Based Polyamine Ligands as Potent Inhibitors of Acetylcholinesterase and Acetylcholinesterase-Induced Amyloid-β Aggregation
Journal of Medicinal Chemistry 2005.0