Similarities and differences in affinity and binding modes of tricyclic pyrimido- and pyrazinoxanthines at human and rat adenosine receptors

Szymańska, Ewa; Drabczyńska, Anna; Karcz, Tadeusz; Müller, Christian; Köse, Meryem; Karolak‐Wojciechowska, J.; Fruziński, Andrzej; Schabikowski, Jakub; Doroż-Płonka, Agata; Handzlik, Jadwiga; Kieć‐Kononowicz, Katarzyna

doi:10.1016/j.bmc.2016.07.028

Cited by 19 publications

(23 citation statements)

References 48 publications

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“…Activation of adenosine A 1 ‐receptors has been shown to protect against renal ischaemia/reperfusion injury in experimental animals (Lee & Emala, ; Lee, Gallos, Nasr, & Emala, ; Park et al, ). However, despite the high homology between the species homologues of the A 1 ‐receptor, there is evidence for species differences in the affinity of certain adenosine receptor ligands (Müller & Jacobson, ; Szymańska et al, ).…”

Section: Introductionmentioning

confidence: 99%

Probe dependence of allosteric enhancers on the binding affinity of adenosine A₁‐receptor agonists at rat and human A₁‐receptors measured using NanoBRET

Cooper

Soave

Jörg

et al. 2019

British J Pharmacology

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Background and Purpose Adenosine is a local mediator that regulates a number of physiological and pathological processes via activation of adenosine A1‐receptors. The activity of adenosine can be regulated at the level of its target receptor via drugs that bind to an allosteric site on the A1‐receptor. Here, we have investigated the species and probe dependence of two allosteric modulators on the binding characteristics of fluorescent and nonfluorescent A1‐receptor agonists. Experimental Approach A Nano‐luciferase (Nluc) BRET (NanoBRET) methodology was used. This used N‐terminal Nluc‐tagged A1‐receptors expressed in HEK293T cells in conjunction with both fluorescent A1‐receptor agonists (adenosine and NECA analogues) and a fluorescent antagonist CA200645. Key Results PD 81,723 and VCP171 elicited positive allosteric effects on the binding affinity of orthosteric agonists at both the rat and human A1‐receptors that showed clear probe dependence. Thus, the allosteric effect on the highly selective partial agonist capadenoson was much less marked than for the full agonists NECA, adenosine, and CCPA in both species. VCP171 and, to a lesser extent, PD 81,723, also increased the specific binding of three fluorescent A1‐receptor agonists in a species‐dependent manner that involved increases in Bmax and pKD. Conclusions and Implications These results demonstrate the power of the NanoBRET ligand‐binding approach to study the effect of allosteric ligands on the binding of fluorescent agonists to the adenosine A1‐receptor in intact living cells. Furthermore, our studies suggest that VCP171 and PD 81,723 may switch a proportion of A1‐receptors to an active agonist conformation (R*).

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Section: Introductionmentioning

confidence: 99%

Probe dependence of allosteric enhancers on the binding affinity of adenosine A₁‐receptor agonists at rat and human A₁‐receptors measured using NanoBRET

Cooper

Soave

Jörg

et al. 2019

British J Pharmacology

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“…The majority of compounds was investigated at both, rat as well as human A 1 and A 2A ARs. This was done because previous studies had revealed major species differences for some classes of AR antagonists between human and rodent receptors (Maemoto et al, 1997 ; Burbiel et al, 2016 ; Szymanska et al, 2016 ). Rats or mice are typically used for preclinical studies.…”

Section: Resultsmentioning

confidence: 99%

Probing Substituents in the 1- and 3-Position: Tetrahydropyrazino-Annelated Water-Soluble Xanthine Derivatives as Multi-Target Drugs With Potent Adenosine Receptor Antagonistic Activity

et al. 2018

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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.

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“…These compounds were obtained by cyclization with amines under different reaction conditions (amount of amine, various organic solvents and different reaction times). The class of tricyclic compounds containing the third ring is considered as bioisosteric analogs of (E)-8-styrylxanthine [27,33,34] having potential antiparkinsonian [28,33], and anticonvulsant activities [35].…”

Section: Anticancer Effectmentioning

confidence: 99%

“…The solvent-free microwave-assisted synthetic protocol was used to insert the amide fragment into the N 9phenylethylpyrimido[2,1-f]purinedione core, obtained by the previously described methods [32,34].…”

Section: Anticancer Effectmentioning

confidence: 99%

Xanthine Scaffold: Available Synthesis Routes to Deliver Diversity by Derivatization

Petrucci

Feroci

Mattiello

et al. 2021

MROC

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: The functionalization of the skeletal systems of heterocycles represents a significant goal for new compounds development. The heterocyclic molecule xanthine (3,7-dihydro-1H-purine-2,6-dione) is a purine base with a bicyclic ring skeleton and four different nitrogen atoms, three of them are -NH groups. The principal derivatives are the well known natural methylxanthines (e.g. caffeine, theophylline and theobromine) that have prominent physiological effects at very low dose. The natural methylated xanthines, theophylline, theobromine and caffeine, are present in different plants such as the tea, cocoa and coffee species. For this reason natural xanthines can be considered as bio-based and renewable starting materials; their use in organic synthesis is strongly recommended in order to carry out sustainable chemistry. Essentially, the xanthine scaffold led to the preparation of numerous compounds very attractive in the pharmaceutical field, and these drugs are commercialized for a wide range of biological activities. The scope of this Mini Review is to consider the use of natural xanthines as starting material in chemical transformations carried out in organic solvents, without the intent to be exhaustive of all the synthetically chemical applications. More information on the chemical and electrochemical reactivity of this structural core in organic solvent can be useful for the scientific community. The effectiveness of natural xanthines can be improved by modifying the structures of these already biologically active compounds.

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Similarities and differences in affinity and binding modes of tricyclic pyrimido- and pyrazinoxanthines at human and rat adenosine receptors

Cited by 19 publications

References 48 publications

Probe dependence of allosteric enhancers on the binding affinity of adenosine A₁‐receptor agonists at rat and human A₁‐receptors measured using NanoBRET

Probe dependence of allosteric enhancers on the binding affinity of adenosine A₁‐receptor agonists at rat and human A₁‐receptors measured using NanoBRET

Probing Substituents in the 1- and 3-Position: Tetrahydropyrazino-Annelated Water-Soluble Xanthine Derivatives as Multi-Target Drugs With Potent Adenosine Receptor Antagonistic Activity

Xanthine Scaffold: Available Synthesis Routes to Deliver Diversity by Derivatization

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Similarities and differences in affinity and binding modes of tricyclic pyrimido- and pyrazinoxanthines at human and rat adenosine receptors

Cited by 19 publications

References 48 publications

Probe dependence of allosteric enhancers on the binding affinity of adenosine A1‐receptor agonists at rat and human A1‐receptors measured using NanoBRET

Probe dependence of allosteric enhancers on the binding affinity of adenosine A1‐receptor agonists at rat and human A1‐receptors measured using NanoBRET

Probing Substituents in the 1- and 3-Position: Tetrahydropyrazino-Annelated Water-Soluble Xanthine Derivatives as Multi-Target Drugs With Potent Adenosine Receptor Antagonistic Activity

Xanthine Scaffold: Available Synthesis Routes to Deliver Diversity by Derivatization

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Probe dependence of allosteric enhancers on the binding affinity of adenosine A₁‐receptor agonists at rat and human A₁‐receptors measured using NanoBRET

Probe dependence of allosteric enhancers on the binding affinity of adenosine A₁‐receptor agonists at rat and human A₁‐receptors measured using NanoBRET