Novel, Dual Target‐Directed Annelated Xanthine Derivatives Acting on Adenosine Receptors and Monoamine Oxidase B

Abstract

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 A2AAR: 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

The Medicinal Chemistry of Caffeine

“…It is approved in Japan and the United States (trade name Nourianz) to treat “off time” in Parkinson’s Disease. Very recent studies have reported novel pyrimido­[2,1- f ]­purinedione based A 2 antagonists as exemplified by 25 ( K i 264 nM), which also act as monoamine oxidase B (MAO-B) inhibitors. , …”

A review of the primary nutritional and environmental factors associated with Parkinson’s disease

“…Finally, we have looked at the combination of adenosine receptor antagonists and MAOB inhibitors. The use of dual-acting ligands targeting both sites induced neuroprotective effects (Kuder et al, 2020). Some studies looked at adenosine receptor antagonists' effect on motor symptoms.…”

Dual Targeting Ligands—Histamine H3 Receptor Ligands with Monoamine Oxidase B Inhibitory Activity—In Vitro and In Vivo Evaluation

“…Thus, the search for multi-target drugs has developed in the last few years [ 1 , 2 ]. This novel strategy in drug design and development focuses on a combination of classical targets (e.g., MAO B inhibition) with new targets e.g., adenosine A 2A receptor blockade [ 3 ] or histamine H 3 R inhibition [ 4 , 5 , 6 , 7 ]. The concept of dual target ligands (DTL) linking blockade of MAO B with inhibition of H 3 R emerged a few years ago when preliminary screening for inhibitory activity toward human MAO B (hMAO B) showed promising inhibition of this enzyme by H 3 R ligands: ciproxifan (IC 50 = 2 µM; Figure 1 ) and DL77 (IC 50 = 19 nM; Figure 1 ) [ 6 , 8 ].…”