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

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