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Novel, Dual Target‐Directed Annelated Xanthine Derivatives Acting on Adenosine Receptors and Monoamine Oxidase B
Author(s) -
Kuder Kamil J.,
Załuski Michał,
Schabikowski Jakub,
Latacz Gniewomir,
OlejarzMaciej Agnieszka,
Jaśko Piotr,
DorozPłonka Agata,
Brockmann Andreas,
Müller Christa E.,
KiećKoowicz Katarzyna
Publication year - 2020
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201900717
Subject(s) - chemistry , monoamine oxidase , receptor , adenosine receptor , stereochemistry , radioligand , docking (animal) , monoamine oxidase b , monoamine oxidase a , adenosine , monoamine neurotransmitter , purine , xanthine oxidase , ligand (biochemistry) , enzyme , biochemistry , serotonin , medicine , nursing , agonist
Annelated purinedione derivatives have been shown to act as possible multiple‐target ligands, addressing adenosine receptors and monoaminooxidases. In this study, based on our previous results, novel annelated pyrimido‐ and diazepino[2,1‐ f ]purinedione derivatives were designed as dual‐target‐directed ligands combining A 2A adenosine receptor (AR) antagonistic activity with blocking monoamine oxidase B. A library of 19 novel compounds was synthesized and biologically evaluated in radioligand binding studies at AR subtypes and for their ability to inhibit MAO‐B. This allowed 9‐(2‐chloro‐6‐fluorobenzyl)‐3‐ethyl‐1‐methyl‐6,7,8,9‐tetrahydropyrimido[2,1‐ f ]purine‐2,4(1 H ,3 H )‐dione ( 13 e ; K i human A 2A AR: 264 nM and IC 50 human MAO‐B: 243 nM) to be identified as the most potent dual‐acting ligand from this series. ADMET parameters were estimated in vitro, and analysis of the structure‐activity relationships was complemented by molecular‐docking studies based on previously published X‐ray structures of the protein targets. Such dual‐acting ligands, by selectively blocking A 2A AR, accompanied by the inhibition of dopamine metabolizing enzyme MAO‐B, might provide symptomatic and neuroprotective effects in, among others, the treatment of Parkinson disease