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: [email protected].
  • 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: [email protected].
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.