4-Oxypiperidine Ethers as Multiple Targeting Ligands at Histamine H3 Receptors and Cholinesterases

This study examines the properties of a novel series of 4-oxypiperidines designed and synthesized as histamine H₃R antagonists/inverse agonists based on the structural modification of two lead compounds, viz., ADS003 and ADS009. The products are intended to maintain a high affinity for H₃R while simultaneously inhibiting AChE or/and BuChE Enzymes. Selected compounds were subjected to hH₃R radioligand displacement and gpH₃R functional assays. Some of the compounds showed nanomolar affinity. The most promising compound in the naphthalene series was ADS031, which contained a benzyl moiety at position 1 of the piperidine ring and displayed 12.5 nM affinity at the hH₃R and the highest inhibitory activity against AChE (IC₅₀ = 1.537 μM). Eight compounds showed over 60% eqBuChE inhibition and hence were qualified for the determination of the IC₅₀ value at eqBuChE; their values ranged from 0.559 to 2.655 μM. Therapy based on a multitarget-directed ligand combining H₃R antagonism with additional AChE/BuChE inhibitory properties might improve cognitive functions in multifactorial Alzheimer's disease.

acetylcholinestrase inhibitor; butyrylcholinesterase inhibitor; histamine H3 receptor; multiple targeting; neurodegenerative disease; polypharmacology.