Abstract
Tetrahydropyrazino-annelated theophylline (1,3-dimethylxanthine) derivatives have previously been shown to display increased water-solubility as compared to the parent xanthines due to their basic character. In the present study, we modified this promising scaffold by replacing the 1,3-dimethyl residues by a variety of alkyl groups including combinations of different substituents in both positions. Substituted benzyl or phenethyl residues were attached to the N8 of the resulting 1,3-dialkyl-tetrahydropyrazino[2,1-f ]purinediones with the aim to obtain multi-target drugs that block human A1 and A2A adenosine receptors (ARs) and monoaminoxidase B (MAO-B). 1,3-Diethyl-substituted derivatives showed high affinity for A1 ARs, e.g., 15d (PSB-18339, 8-m-bromobenzyl-substituted) displayed a Ki value of 13.6 nM combined with high selectivity. 1-Ethyl-3-propargyl-substituted derivatives exhibited increased A2A AR affinity. The 8-phenethyl derivative 20h was selective for the A2A AR (Ki 149 nM), while the corresponding 8-benzyl-substituted compound 20e (PSB-1869) blocked A1 and A2A ARs with equal potency (Ki A1, 180 nM; A2A, 282 nM). The 1-ethyl-3-methyl-substituted derivative 16a (PSB-18405) bearing a m,p-dichlorobenzyl residue at N8 blocked all three targets, A1 ARs (Ki 396 nM), A2A ARs (Ki 1,620 nM), and MAO-B (IC50 106 nM) with high selectivity vs. the other subtypes (A2B and A3 ARs, MAO-A), and can thus be considered as a multi-target drug. Our findings were rationalized by molecular docking studies based on previously published X-ray structures of the protein targets. The new drugs have potential for the treatment of neurodegenerative diseases, in particular Parkinson's disease.
Highlights
Adenosine receptors (ARs), those of the A2A subtype, have emerged as new targets for neurodegenerative diseases, in particular for Parkinson’s (PD) and Alzheimer’s disease (AD)
The concept of multi-target drugs interacting simultaneously with two or more pharmacological targets was proposed as a strategy for the treatment of complex diseases such as cancer, psychiatric disorders and neurodegenerative diseases (Geldenhuys and Van Der Schyf, 2013)
10 μL of the substance solution was injected into a Phenomenex Luna C18 HPLC column (50 × 2.00 mm, particle size 3 μm) and elution was performed for 30 min at a flow rate of 250 μL/min with a gradient of water: methanol either containing 2 mM ammonium acetate from 90:10 up to 0:100, starting the gradient after 10 min or containing 2 mM ammonium acetate and 0.1% formic acid from 90:10 up to 0:100, starting the gradient after 10 min
Summary
Adenosine receptors (ARs), those of the A2A subtype, have emerged as new targets for neurodegenerative diseases, in particular for Parkinson’s (PD) and Alzheimer’s disease (AD). The 8-stryrylxanthine derivative istradefylline (Nouriast R , 1, Figure 1) was approved in Japan as adjunctive treatment of PD in combination with levodopa (Dungo and Deeks, 2013). The consumption of caffeine (2), which is a weakly potent and non-selective AR antagonist (Figure 1), was found to protect from PD and AD as demonstrated in a number of animal models as well as in large epidemiological studies in humans (Chen and Chern, 2011; Flaten et al, 2014). The concept of multi-target drugs interacting simultaneously with two or more pharmacological targets was proposed as a strategy for the treatment of complex diseases such as cancer, psychiatric disorders and neurodegenerative diseases (Geldenhuys and Van Der Schyf, 2013). Multi-target drugs may exhibit high efficacy due to synergistic effects, show a reduced risk of side effects, and result in improved compliance, especially in elderly patients, as compared to combination therapies of two or more different drugs
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