Discovery of new dual butyrylcholinesterase (BuChE) inhibitors and 5-HT7 receptor antagonists as compounds used to treat Alzheimer’s disease symptoms

Abstract

Alzheimer's disease is a neurodegenerative condition with no effective cure, and current therapies, like donepezil, only alleviate symptoms. Research has explored cholinesterase inhibitors and strategies targeting tau protein, often combining inhibitors with 5-HT receptor antagonists, particularly 5-HT₆. However, dual-action BuChE inhibitors and 5-HT₇ antagonists have not been studied until now. This study evaluated such compounds in an animal model, focusing on two candidates: compound 18 (BuChE IC₅₀ = 4.75 μM; 5-HT₇ K_i = 7 nM) and compound 50 (BuChE IC₅₀ = 2.53 μM; 5-HT₇ K_i = 1 nM). Compound 50 showed robust cognitive improvements, enhancing memory consolidation and acquisition, particularly in reversing scopolamine-induced deficits. In contrast, compound 18 exhibited limited or dose-dependent efficacy, potentially limiting its applicability. These findings highlight the strong potential of compound 50 for cognitive enhancement therapies and suggest it warrants further investigation.