Conjugation of Aminoadamantane and γ-Carboline Pharmacophores Gives Rise to Unexpected Properties of Multifunctional Ligands

Molecules

Rudy J. Richardson¹  Vladimir P. Fisenko²  Vladimir L. Zamoyski³  Elena V. Rudakova³  Lyudmila G. Dubova³  Alexey Yu. Aksinenko³  Vladimir V. Grigoriev³  Elena A. Pushkareva³  Elena F. Shevtsova³  Sergey O. Bachurin³  Nadezhda V. Kovaleva³  Elena V. Bovina³  Tatiana V. Goreva³  Pavel N. Shevtsov³  Natalia P. Boltneva³  Tatiana A. Epishina³  Alexey V. Gabrelyan³  Galina F. Makhaeva³  Sofya V. Lushchekina³ 

[1] Department of Environmental Health Sciences, University of Michigan, Ann Arbor, MI 48109, USA;I.M.Sechenov First Moscow State Medical University, 8 Build. 2 Trubetskaya Str., 119991 Moscow, Russia;Institute of Physiologically Active Compounds, Russian Academy of Sciences, 142432 Chernogolovka, Russia;

关键词: multifunctional agents;    Alzheimer’s disease;    cholinesterases;    NMDA receptor;    mitochondrial permeability transition (MPT) pore;    microtubules;   

DOI  :  10.3390/molecules26185527

来源: DOAJ

【 摘 要 】

A new series of conjugates of aminoadamantane and γ-carboline, which are basic scaffolds of the known neuroactive agents, memantine and dimebon (Latrepirdine) was synthesized and characterized. Conjugates act simultaneously on several biological structures and processes involved in the pathogenesis of Alzheimer’s disease and some other neurodegenerative disorders. In particular, these compounds inhibit enzymes of the cholinesterase family, exhibiting higher inhibitory activity against butyrylcholinesterase (BChE), but having almost no effect on the activity of carboxylesterase (anti-target). The compounds serve as NMDA-subtype glutamate receptor ligands, show mitoprotective properties by preventing opening of the mitochondrial permeability transition (MPT) pore, and act as microtubule stabilizers, stimulating the polymerization of tubulin and microtubule-associated proteins. Structure–activity relationships were studied, with particular attention to the effect of the spacer on biological activity. The synthesized conjugates showed new properties compared to their prototypes (memantine and dimebon), including the ability to bind to the ifenprodil-binding site of the NMDA receptor and to occupy the peripheral anionic site of acetylcholinesterase (AChE), which indicates that these compounds can act as blockers of AChE-induced β-amyloid aggregation. These new attributes of the conjugates represent improvements to the pharmacological profiles of the separate components by conferring the potential to act as neuroprotectants and cognition enhancers with a multifunctional mode of action.

【 授权许可】

Unknown