Interaction of 7-Methoxytacrine-Adamantylamine Cholinesterase Inhibitors with Nicotinic and Muscarinic Acetylcholine Receptors

Abstract

Acetylcholinesterase inhibitors (AChEI) and the N-methyl-D-aspartate (NMDA) receptor antagonist memantine are among the few FDA-approved drugs for Alzheimer's disease. In effort to develop multi-target (AChE-NMDA)-directed ligands for the treatment of Alzheimer's disease, a series 7-Methoxytacrine-Adamantylamine thiourea heterodimers have been synthesized and evaluated for their effects as AChEI (Spilovska et. al. 2013, Molecules 18, 2397-2418). In this report, we extend their pharmacological characterization by examining their effects on neuronal and muscle-type nicotinic acetylcholine receptors (nAChR) and muscarinic acetylcholine receptors (mAChR). We also compare their pharmacology to 7-Methoxytacrine-Adamantylamine urea heterodimers. 7-Methoxytacrine-Adamantylamine thiourea derivatives containing 2-8 carbon linkers inhibited AChE and butyrylcholinesterase (BChE) with high potency (IC50, 0.5-6 μM), whereas 7-Methoxytacrine-Adamantylamine urea derivatives inhibited AChE with higher potency than BChE. None of the tested compound potentiated M1 mAChR or nAChRs responses. They have minimal effects on acetylcholine-induced currents in Xenopus oocytes expressing neuronal α4β2 nAChR and inhibited M1 mAChR at higher concentrations (IC50s >10 μM). At concentration that inhibit AChE, both thiourea and urea derivatives inhibited acetylcholine-induced currents in Xenopus oocytes expressing muscle-type AChRs. Our preliminary results also suggest that the length of the carbon linker affect 7-Methoxytacrine-Adamantylamine urea interactions with AChRs, and further modifications of their structure are expected to yield compounds with more favorable pharmacological profiles.