Novel, Dual Target-Directed Annelated Xanthine Derivatives Acting on Adenosine Receptors and Monoamine Oxidase B.
Kamil J KuderMichał ZałuskiJakub SchabikowskiGniewomir LataczAgnieszka Olejarz-MaciejPiotr JaśkoAgata Doroz-PłonkaAndreas BrockmannChrista Elisabeth MüllerKatarzyna Kieć-KononowiczPublished in: ChemMedChem (2020)
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 A2A 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(1H,3H)-dione (13 e; Ki human A2A AR: 264 nM and IC50 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 A2A 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.
Keyphrases
- molecular docking
- parkinson disease
- endothelial cells
- deep brain stimulation
- photodynamic therapy
- molecular dynamics simulations
- uric acid
- induced pluripotent stem cells
- pluripotent stem cells
- systematic review
- structure activity relationship
- randomized controlled trial
- magnetic resonance
- computed tomography
- case control
- small molecule
- protein protein
- metabolic syndrome
- radiation therapy
- locally advanced
- anti inflammatory
- combination therapy
- contrast enhanced
- meta analyses
- oxide nanoparticles