Huprine Y - Tryptophan heterodimers with potential implication to Alzheimer's disease treatment

Bioorg Med Chem Lett. 2021 Jul 1:43:128100. doi: 10.1016/j.bmcl.2021.128100.

Eva Mezeiova ¹, Martina Hrabinova ², Vendula Hepnarova ², Daniel Jun ², Jana Janockova ³, Lubica Muckova ², Lukas Prchal ³, Zdena Kristofikova ⁴, Tomas Kucera ⁵, Lukas Gorecki ², Katarina Chalupova ⁶, Jiri Kunes ⁷, Jana Hroudova ⁸, Ondrej Soukup ⁹, Jan Korabecny ¹⁰

Affiliations

1 Biomedical Research Centre, University Hospital Hradec Kralove, Sokolska 581, 500 05 Hradec Kralove, Czech Republic; National Institute of Mental Health, Topolova 748, 250 67 Klecany, Czech Republic.
2 Biomedical Research Centre, University Hospital Hradec Kralove, Sokolska 581, 500 05 Hradec Kralove, Czech Republic; Department of Toxicology and Military Pharmacy, Faculty of Military Health Sciences, Trebesska 1575, 500 01 Hradec Kralove, Czech Republic.
3 Biomedical Research Centre, University Hospital Hradec Kralove, Sokolska 581, 500 05 Hradec Kralove, Czech Republic.
4 National Institute of Mental Health, Topolova 748, 250 67 Klecany, Czech Republic.
5 Department of Toxicology and Military Pharmacy, Faculty of Military Health Sciences, Trebesska 1575, 500 01 Hradec Kralove, Czech Republic.
6 Biomedical Research Centre, University Hospital Hradec Kralove, Sokolska 581, 500 05 Hradec Kralove, Czech Republic; Department of Chemistry, University of Hradec Kralove, Rokytanskeho 62, 500 03 Hradec Kralove, Czech Republic.
7 Department of Organic and Bioorganic Chemistry, Faculty of Pharmacy in Hradec Kralove, Charles University in Prague, Heyrovskeho 1203, 500 05 Hradec Kralove, Czech Republic.
8 Department of Psychiatry, First Faculty of Medicine, Charles University and General University Hospital in Prague, Ke Karlovu 11, 120 00 Prague 2, Czech Republic; Institute of Pharmacology, First Faculty of Medicine, Charles University and General University Hospital in Prague, Albertov 4, 128 00, Prague 2, Czech Republic.
9 Biomedical Research Centre, University Hospital Hradec Kralove, Sokolska 581, 500 05 Hradec Kralove, Czech Republic; Department of Toxicology and Military Pharmacy, Faculty of Military Health Sciences, Trebesska 1575, 500 01 Hradec Kralove, Czech Republic. Electronic address: ondrej.soukup@fnhk.cz.
10 Biomedical Research Centre, University Hospital Hradec Kralove, Sokolska 581, 500 05 Hradec Kralove, Czech Republic; Department of Toxicology and Military Pharmacy, Faculty of Military Health Sciences, Trebesska 1575, 500 01 Hradec Kralove, Czech Republic. Electronic address: jan.korabecny@fnhk.cz.

PMID: 33984470 DOI: 10.1016/j.bmcl.2021.128100

Abstract

The search for novel and effective therapeutics for Alzheimer's disease (AD) is the main quest that remains to be resolved. The goal is to find a disease-modifying agent able to confront the multifactorial nature of the disease positively. Herewith, a family of huprineY-tryptophan heterodimers was prepared, resulting in inhibition of cholinesterase and neuronal nitric oxide synthase Enzymes, with effect against amyloid-beta (Aβ) and potential ability to cross the blood-brain barrier. Their cholinesterase pattern of behavior was inspected using kinetic analysis in tandem with docking studies. These heterodimers exhibited a promising pharmacological profile with strong implication in AD.

Keywords

Acetylcholinesterase; Alzheimer's disease; Amyloid-beta; Multi-target directed ligands; huprine Y; l-Tryptophan.

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