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

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.

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