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TACRINE HYBRIDS - NMDAR antagonist

技术优势

Hybrid molecules represent a new and different strategy in the treatment of AD. We suppose that these compounds are able to hit additional targets relevant to AD and thus succeed in overcoming the multifactorial pathogenesis of this disease. These compounds may be beneficial since they would be expected to lessen the hazard of drug-drug interactions and simplify their pharmacodynamic and pharmacokinetic studies.

技术应用

AlzheimerΓÇÖs disease (AD) is the most common cause of dementia in people aged 60 years and older, and accounts for approximately 75% of the total dementia cases worldwide. The continuous research in this field has contributed to delineate AD as a multifactorial syndrome with several biological targets involved in its etiology. Thus the curative paradigm of one-compound one-target that has been followed so far has not reached the desired expectations. The research focus moved towards single hybrid molecule targeting two or more mechanisms involved in disease pathophysiology.

详细技术说明

A combination of the AChE inhibitor and N-methyl-D-aspartate receptor (NMDAR) antagonist (memantine) is now a standard treatment of AD. Therefore there were synthetized hybrid molecules affecting both targets ΓÇô cholinesterases and NMDAR. Our hybrids are able to inhibit acetylcholinesterase and butyrylcholinesterase and furthermore inhibit excessive calcium influx induced by chronic overstimulation of the NMDAR in AD patients.

*Abstract

Tacrine is the first FDA approved drug for the symptomatic treatment of mild to moderate AD. Although it has some side effects like gastrointestinal disorders andhepatotoxicity, tacrine remains a reference therapeutic agent. Treatment for AD has to be taken life-long, so it was of prior importance to build up safer and more effective AChE inhibitors. The research focus in AD field moved towards single molecule targeting two or more pathogenic mechanisms involved in neuronal death. Over the last few years, medicinal chemists have been paying attention tothe design and synthesis of the hybrid molecules that are comprised of two pharmacophores from well-established chemical scaffolds endowed with requisite biological activities in a single entity. The hybrid-based approach has grown to be a central point in the medicinal chemistry field. Various important pharmacophores used for AD have been combined with selected biologically active molecules to get homo- and heterodimers with improved efficacy with additional supplementary actions. Our tacrine hybrids showed potent inhibition of cholinesterases and additional modulation of Ca2+ influx leaving the channel relatively open for neurotransmission at low stimulation rates.

*Principal Investigation

Name: Jan Korabecny, Ph.D.

Department: Biomedical Research Centre

Name: Kamil Kuca, prof.

Department: Biomedical Research Centre

Name: Eugenie Nepovimova

Department: Biomedical Research Centre

Name: Ondrej Soukup, Ph.D.

Department: Biomedical Research Centre

国家/地区

美国