Publications by authors named "Sonja Hinz"

39 Publications

Adenosine AR/AR Antagonists Enabling Additional HR Antagonism for the Treatment of Parkinson's Disease.

J Med Chem 2021 Jun 9;64(12):8246-8262. Epub 2021 Jun 9.

Institute of Pharmaceutical and Medicinal Chemistry, Heinrich Heine University Duesseldorf, Universitaets street 1, 40225 Duesseldorf, Germany.

Adenosine A/A receptors (AR/AR) represent targets in nondopaminergic treatment of motor disorders such as Parkinson's disease (PD). As an innovative strategy, multitargeting ligands (MTLs) were developed to achieve comprehensive PD therapies simultaneously addressing comorbid symptoms such as sleep disruption. Recognizing the wake-promoting capacity of histamine H receptor (HR) antagonists in combination with the "caffeine-like effects" of AR/AR antagonists, we designed AR/AR/HR MTLs, where a piperidino-/pyrrolidino(propyloxy)phenyl HR pharmacophore was introduced with overlap into an adenosine antagonist arylindenopyrimidine core. These MTLs showed distinct receptor binding profiles with overall nanomolar HR affinities ( < 55 nM). Compound (, (AR) = 11.5 nM, (AR) = 7.25 nM) and (, (AR) = 11.2 nM, (AR) = 4.01 nM) were evaluated . l-DOPA-induced dyskinesia was improved after administration of compound (1 mg kg, i.p. rats). Compound (2 mg kg, p.o. mice) increased wakefulness representing novel pharmacological tools for PD therapy.
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http://dx.doi.org/10.1021/acs.jmedchem.0c00914DOI Listing
June 2021

Synthesis of Novel Fluorinated Xanthine Derivatives with High Adenosine A Receptor Binding Affinity.

Pharmaceuticals (Basel) 2021 May 19;14(5). Epub 2021 May 19.

Helmholtz-Zentrum Dresden-Rossendorf, Institute of Radiopharmaceutical Cancer Research, Department of Neuroradiopharmaceuticals, 04318 Leipzig, Germany.

The G protein-coupled adenosine A receptor is suggested to be involved in various pathological processes accompanied by increased levels of adenosine as found in inflammation, hypoxia, and cancer. Therefore, the adenosine A receptor is currently in focus as a novel target for cancer therapy as well as for noninvasive molecular imaging via positron emission tomography (PET). Aiming at the development of a radiotracer labeled with the PET radionuclide fluorine-18 for imaging the adenosine A receptor in brain tumors, one of the most potent and selective antagonists, the xanthine derivative PSB-603, was selected as a lead compound. As initial biodistribution studies in mice revealed a negligible brain uptake of [H]PSB-603 (SUV: 0.2), structural modifications were performed to optimize the physicochemical properties regarding blood-brain barrier penetration. Two novel fluorinated derivatives bearing a 2-fluoropyridine () moiety and a 4-fluoro-piperidine () moiety were synthesized, and their affinity towards the four adenosine receptor subtypes was determined in competition binding assays. Both compounds showed high affinity towards the adenosine A receptor ( () = 9.97 ± 0.86 nM; () = 12.3 ± 3.6 nM) with moderate selectivity versus the other adenosine receptor subtypes.
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http://dx.doi.org/10.3390/ph14050485DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8161391PMC
May 2021

Molecular and Pharmacological Characterization of the Interaction between Human Geranylgeranyltransferase Type I and Ras-Related Protein Rap1B.

Int J Mol Sci 2021 Mar 2;22(5). Epub 2021 Mar 2.

Center for Biomedical Education and Research (ZBAF), Faculty of Health, Institute of Pharmacology and Toxicology, School of Medicine, University of Witten/Herdecke, 58453 Witten, Germany.

Geranylgeranyltransferase type-I (GGTase-I) represents an important drug target since it contributes to the function of many proteins that are involved in tumor development and metastasis. This led to the development of GGTase-I inhibitors as anti-cancer drugs blocking the protein function and membrane association of e.g., Rap subfamilies that are involved in cell differentiation and cell growth. In the present study, we developed a new NanoBiT assay to monitor the interaction of human GGTase-I and its substrate Rap1B. Different Rap1B prenylation-deficient mutants (C181G, C181S, and ΔCQLL) were designed and investigated for their interaction with GGTase-I. While the Rap1B mutants C181G and C181S still exhibited interaction with human GGTase-I, mutant ΔCQLL, lacking the entire CAAX motif (defined by a cysteine residue, two aliphatic residues, and the C-terminal residue), showed reduced interaction. Moreover, a specific, peptidomimetic and competitive CAAX inhibitor was able to block the interaction of Rap1B with GGTase-I. Furthermore, activation of both Gα-coupled human adenosine receptors, A (AAR) and A (AAR), increased the interaction between GGTase-I and Rap1B, probably representing a way to modulate prenylation and function of Rap1B. Thus, AAR and AAR antagonists might be promising candidates for therapeutic intervention for different types of cancer that overexpress Rap1B. Finally, the NanoBiT assay provides a tool to investigate the pharmacology of GGTase-I inhibitors.
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http://dx.doi.org/10.3390/ijms22052501DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7958859PMC
March 2021

A Cellular Assay for the Identification and Characterization of Connexin Gap Junction Modulators.

Int J Mol Sci 2021 Jan 31;22(3). Epub 2021 Jan 31.

PharmaCenter Bonn, Pharmaceutical Institute, Pharmaceutical & Medicinal Chemistry, Rheinische Friedrich-Wilhelms-Universität Bonn, An der Immenburg 4, D-53121 Bonn, Germany.

Connexin gap junctions (Cx GJs) enable the passage of small molecules and ions between cells and are therefore important for cell-to-cell communication. Their dysfunction is associated with diseases, and small molecules acting as modulators of GJs may therefore be useful as therapeutic drugs. To identify GJ modulators, suitable assays are needed that allow compound screening. In the present study, we established a novel assay utilizing HeLa cells recombinantly expressing Cx43. Donor cells additionally expressing the Gs protein-coupled adenosine A receptor, and biosensor cells expressing a cAMP-sensitive GloSensor luciferase were established. Adenosine A receptor activation in the donor cells using a selective agonist results in intracellular cAMP production. The negatively charged cAMP migrates via the Cx43 gap junctions to the biosensor cells and can there be measured by the cAMP-dependent luminescence signal. Cx43 GJ modulators can be expected to impact the transfer of cAMP from the donor to the biosensor cells, since cAMP transit is only possible via GJs. The new assay was validated by testing the standard GJ inhibitor carbenoxolon, which showed a concentration-dependent inhibition of the signal and an IC value that was consistent with previously reported values. The assay was demonstrated to be suitable for high-throughput screening.
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http://dx.doi.org/10.3390/ijms22031417DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7866863PMC
January 2021

Nucleotide P2Y receptor agonists are in vitro and in vivo prodrugs of A/A adenosine receptor agonists: implications for roles of P2Y and A/A receptors in physiology and pathology.

Purinergic Signal 2020 12 31;16(4):543-559. Epub 2020 Oct 31.

University of Texas Health at San Antonio, San Antonio, TX, USA.

Rapid phosphoester hydrolysis of endogenous purine and pyrimidine nucleotides has challenged the characterization of the role of P2 receptors in physiology and pathology. Nucleotide phosphoester stabilization has been pursued on a number of medicinal chemistry fronts. We investigated the in vitro and in vivo stability and pharmacokinetics of prototypical nucleotide P2Y receptor (P2YR) agonists and antagonists. These included the riboside nucleotide agonist 2-methylthio-ADP and antagonist MRS2179, as well as agonist MRS2365 and antagonist MRS2500 containing constrained (N)-methanocarba rings, which were previously reported to form nucleotides that are more slowly hydrolyzed at the α-phosphoester compared with the ribosides. In vitro incubations in mouse and human plasma and blood demonstrated the rapid hydrolysis of these compounds to nucleoside metabolites. This metabolism was inhibited by EDTA to chelate divalent cations required by ectonucleotidases for nucleotide hydrolysis. This rapid hydrolysis was confirmed in vivo in mouse pharmacokinetic studies that demonstrate that MRS2365 is a prodrug of the nucleoside metabolite AST-004 (MRS4322). Furthermore, we demonstrate that the nucleoside metabolites of MRS2365 and 2-methylthio-ADP are adenosine receptor (AR) agonists, notably at A and AARs. In vivo efficacy of MRS2365 in murine models of traumatic brain injury and stroke can be attributed to AR activation by its nucleoside metabolite AST-004, rather than P2YR activation. This research suggests the importance of reevaluation of previous in vitro and in vivo research of P2YRs and P2XRs as there is a potential that the pharmacology attributed to nucleotide agonists is due to AR activation by active nucleoside metabolites.
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http://dx.doi.org/10.1007/s11302-020-09732-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7855190PMC
December 2020

8-Benzylaminoxanthine scaffold variations for selective ligands acting on adenosine A receptors. Design, synthesis and biological evaluation.

Bioorg Chem 2020 08 19;101:104033. Epub 2020 Jun 19.

Department of Technology and Biotechnology of Drugs, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9, 30688 Kraków, Poland. Electronic address:

A library of 34 novel compounds based on a xanthine scaffold was explored in biological studies for interaction with adenosine receptors (ARs). Structural modifications of the xanthine core were introduced in the 8-position (benzylamino and benzyloxy substitution) as well as at N1, N3, and N7 (small alkyl residues), thereby improving affinity and selectivity for the A AR. The compounds were characterized by radioligand binding assays, and our study resulted in the development of the potent A AR ligands including 8-((6-chloro-2-fluoro-3-methoxybenzyl)amino)-1-ethyl-3,7-dimethyl-3,7-dihydro-1H-purine-2,6-dione (12d; K human AAR: 68.5 nM) and 8-((2-chlorobenzyl)amino)-1-ethyl-3,7-dimethyl-3,7-dihydro-1H-purine-2,6-dione (12h; K human AAR: 71.1 nM). Moreover, dual A/AAR ligands were identified in the group of 1,3-diethyl-7-methylxanthine derivatives. Compound 14b displayed K values of 52.2 nM for the AAR and 167 nM for the AAR. Selected AAR ligands were further evaluated as inactive for inhibition of monoamine oxidase A, B and isoforms of phosphodiesterase-4B1, -10A, which represent classical targets for xanthine derivatives. Therefore, the developed 8-benzylaminoxanthine scaffold seems to be highly selective for AR activity and relevant for potent and selective A ligands. Compound 12d with high selectivity for ARs, especially for the AAR subtype, evaluated in animal models of inflammation has shown anti-inflammatory activity. Investigated compounds were found to display high selectivity and may therefore be of high interest for further development as drugs for treating cancer or neurodegenerative diseases.
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http://dx.doi.org/10.1016/j.bioorg.2020.104033DOI Listing
August 2020

Development of a Radiofluorinated Adenosine A Receptor Antagonist as Potential Ligand for PET Imaging.

Int J Mol Sci 2020 Apr 30;21(9). Epub 2020 Apr 30.

Department of Neuroradiopharmaceuticals, Institute of Radiopharmaceutical Cancer Research, Helmholtz-Zentrum Dresden-Rossendorf, 04318 Leipzig, Germany.

The adenosine A receptor has been proposed as a novel therapeutic target in cancer, as its expression is drastically elevated in several tumors and cancer cells. Noninvasive molecular imaging via positron emission tomography (PET) would allow the in vivo quantification of this receptor in pathological processes and most likely enable the identification and clinical monitoring of respective cancer therapies. On the basis of a bicyclic pyridopyrimidine-2,4-dione core structure, the new adenosine A receptor ligand was synthesized, containing a 2-fluoropyridine moiety suitable for labeling with the short-lived PET radionuclide fluorine-18. Compound showed a high binding affinity for the human A receptor (K(A) = 2.51 nM), along with high selectivities versus the A, A, and A receptor subtypes. Therefore, it was radiofluorinated via nucleophilic aromatic substitution of the corresponding nitro precursor using [F]F/K/KCO in DMSO at 120 °C. Metabolic studies of in mice revealed about 60% of radiotracer intact in plasma at 30 minutes p.i. A preliminary PET study in healthy mice showed an overall biodistribution of , corresponding to the known ubiquitous but low expression of the A receptor. Consequently, represents a novel PET radiotracer with high affinity and selectivity toward the adenosine A receptor and a suitable in vivo profile. Subsequent studies are envisaged to investigate the applicability of to detect alterations in the receptor density in certain cancer-related disease models.
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http://dx.doi.org/10.3390/ijms21093197DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7246765PMC
April 2020

Discovery and Structure Relationships of Salicylanilide Derivatives as Potent, Non-acidic P2X1 Receptor Antagonists.

J Med Chem 2020 06 27;63(11):6164-6178. Epub 2020 May 27.

PharmaCenter Bonn, Pharmaceutical Institute, Pharmaceutical & Medicinal Chemistry, University of Bonn, An der Immenburg 4, D-53121 Bonn, Germany.

Antagonists for the ATP-gated ion channel receptor P2X1 have potential as antithrombotics and for treating hyperactive bladder and inflammation. In this study, salicylanilide derivatives were synthesized based on a screening hit. P2X1 antagonistic potency was assessed in 1321N1 astrocytoma cells stably transfected with the human P2X1 receptor by measuring inhibition of the ATP-induced calcium influx. Structure-activity relationships were analyzed, and selectivity versus other P2X receptor subtypes was assessed. The most potent compounds, -[3,5-bis(trifluoromethyl)phenyl]-5-chloro-2-hydroxybenzamide (, IC 0.0192 μM) and -[3,5-bis(trifluoromethyl)phenyl]-4-chloro-2-hydroxybenzamide (, IC 0.0231 μM), displayed >500-fold selectivity versus P2X2 and P2X3, and 10-fold selectivity versus P2X4 and P2X7 receptors, and inhibited collagen-induced platelet aggregation. They behaved as negative allosteric modulators, and molecular modeling studies suggested an extracellular binding site. Besides selective P2X1 antagonists, compounds with ancillary P2X4 and/or P2X7 receptor inhibition were discovered. These compounds represent the first potent, non-acidic, allosteric P2X1 receptor antagonists reported to date.
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http://dx.doi.org/10.1021/acs.jmedchem.0c00435DOI Listing
June 2020

Cell-permeable high-affinity tracers for G proteins provide structural insights, reveal distinct binding kinetics and identify small molecule inhibitors.

Br J Pharmacol 2020 04 11;177(8):1898-1916. Epub 2020 Feb 11.

PharmaCenter Bonn, Pharmaceutical Institute, Pharmaceutical Chemistry I, University of Bonn, Bonn, Germany.

Background And Purpose: G proteins are intracellular switches that transduce and amplify extracellular signals from GPCRs. The G protein subtypes, which are coupled to PLC activation, can act as oncogenes, and their expression was reported to be up-regulated in cancer and inflammatory diseases. G inhibition may be an efficient therapeutic strategy constituting a new level of intervention. However, diagnostic tools and therapeutic drugs for G proteins are lacking.

Experimental Approach: We have now developed G -specific, cell-permeable H-labelled high-affinity probes based on the macrocyclic depsipeptides FR900359 (FR) and YM-254890 (YM). The tracers served to specifically label and quantify G proteins in their native conformation in cells and tissues with high accuracy.

Key Results: FR and YM displayed low nanomolar affinity for Gα , Gα and Gα expressed in CRISPR/Cas9 Gα -knockout cells, but not for Gα . The two structurally very similar tracers showed strikingly different dissociation kinetics, which is predicted to result in divergent biological effects. Computational studies suggested a "dowel" effect of the pseudoirreversibly binding FR. A high-throughput binding assay led to the discovery of novel G inhibitors, which inhibited G signalling in recombinant cells and primary murine brown adipocytes, resulting in enhanced differentiation.

Conclusions And Implications: The Gq protein inhibitors YM and FR are pharmacologically different despite similar structures. The new versatile tools and powerful assays will contribute to the advancement of the rising field of G protein research.
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http://dx.doi.org/10.1111/bph.14960DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7070167PMC
April 2020

A and A adenosine receptors: The extracellular loop 2 determines high (A) or low affinity (A) for adenosine.

Biochem Pharmacol 2020 02 18;172:113718. Epub 2019 Nov 18.

PharmaCenter Bonn, Pharmaceutical Institute, Pharmaceutical & Medicinal Chemistry, University of Bonn, An der Immenburg 4, D-53121 Bonn, Germany. Electronic address:

A and A adenosine receptors (ARs) are closely related G protein-coupled receptor subtypes, which represent important (potential) drug targets. Despite their almost identical binding sites for adenosine, AARs are activated by low (nanomolar) adenosine concentrations, while AARs require micromolar concentrations. In the present study, we exchanged the extracellular loop 2 (ECL2) of the human AAR for that of the AAR. The resulting chimeric A(ECL2-A)AR was investigated in radioligand binding and cAMP accumulation assays in comparison to the wildtype AAR. While the ribose-modified adenosine analog N-ethylcarboxamidoadenosine (NECA) and its 2-substituted derivative CGS-21680 did not exhibit significant changes, adenosine showed dramatically reduced potency and affinity for the A(ECL2-A)AR mutant displaying similarly low potency as for the wt AAR. Supervised molecular dynamics simulation studies predicted a meta-binding site with high affinity for adenosine, but not for NECA, which may contribute to the observed effects.
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http://dx.doi.org/10.1016/j.bcp.2019.113718DOI Listing
February 2020

A Adenosine Receptor Antagonists with Picomolar Potency.

J Med Chem 2019 04 15;62(8):4032-4055. Epub 2019 Apr 15.

Pharmaceutical Chemistry I, PharmaCenter Bonn, Pharmaceutical Institute , Rheinische Friedrich-Wilhelms-Universitat Bonn , An der Immenburg 4 , D-53121 Bonn , Germany.

The A adenosine receptor (AAR) was proposed as a novel target for the (immuno)therapy of cancer since AAR blockade results in antiproliferative, antiangiogenic, antimetastatic, and immunostimulatory effects. In this study, we explored the structure-activity relationships of xanthin-8-yl-benzenesulfonamides mainly by introducing a variety of linkers and substituents attached to the sulfonamide residue. A new, convergent strategy was established, which facilitated the synthesis of the target compounds. Many of the new compounds exhibited subnanomolar affinity for the AAR combined with high selectivity. Functional groups were introduced, which will allow the attachment of dyes and other reporter groups. 8-(4-((4-(4-Bromophenyl)piperazin-1-yl)sulfonyl)phenyl)-1-propylxanthine (34, PSB-1901) was the most potent A-antagonist ( K 0.0835 nM, K 0.0598 nM, human AAR) with >10 000-fold selectivity versus all other AR subtypes. It was similarly potent and selective at the mouse AAR, making it a promising tool for preclinical studies. Computational studies predicted halogen bonding to contribute to the outstanding potency of 34.
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http://dx.doi.org/10.1021/acs.jmedchem.9b00071DOI Listing
April 2019

Novel multi-target directed ligands based on annelated xanthine scaffold with aromatic substituents acting on adenosine receptor and monoamine oxidase B. Synthesis, in vitro and in silico studies.

Bioorg Med Chem 2019 04 2;27(7):1195-1210. Epub 2019 Feb 2.

Department of Technology and Biotechnology of Drugs, Faculty of Pharmacy, Jagiellonian University Medical College, Kraków, Poland. Electronic address:

N9-Benzyl-substituted imidazo-, pyrimido- and 1,3-diazepino[2,1-f]purinediones were designed as dual-target-directed ligands combining A adenosine receptor (AR) antagonistic activity with blockade of monoamine oxidase B (MAO-B). A library of 37 novel compounds was synthesized and biologically evaluated in radioligand binding studies at AR subtypes and for their ability to inhibit MAO-B. A systematic modification of the tricyclic structures based on a xanthine core by enlargement of the third heterocyclic ring or attachment of various substituted benzyl moieties resulted in the development of 9-(2-chloro-6-fluorobenzyl)-1,3-dimethyl-6,7,8,9-tetrahydropyrimido[2,1-f]purine-2,4(1H,3H)-dione (9u; K human AAR: 189 nM and IC human MAO-B: 570 nM) as the most potent dual acting ligand of the series displaying high selectivity versus related targets. Moreover, some potent, selective MAO-B inhibitors were identified in the group of pyrimido- and 1,3-diazepino[2,1-f]purinediones. Compound 10d (10-(3,4-dichlorobenzyl)-1,3-dimethyl-7,8,9,10-tetrahydro-1H-[1,3]diazepino[2,1-f]purine-2,4(3H,6H)-dione) displayed an IC value at human MAO-B of 83 nM. Analysis of structure-activity relationships was complemented by molecular docking studies based on previously published X-ray structures of the protein targets. An extended biological profile was determined for selected compounds including in vitro evaluation of potential hepatotoxicity calculated in silico and antioxidant properties as an additional desirable activity. The new molecules acting as dual target drugs may provide symptomatic relief as well as disease-modifying effects for neurodegenerative diseases, in particular Parkinson's disease.
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http://dx.doi.org/10.1016/j.bmc.2019.02.004DOI Listing
April 2019

Tricyclic xanthine derivatives containing a basic substituent: adenosine receptor affinity and drug-related properties.

Medchemcomm 2018 Jun 14;9(6):951-962. Epub 2018 May 14.

Department of Technology and Biotechnology of Drugs , Faculty of Pharmacy , Jagiellonian University Medical College , Kraków , Poland . Email: ; ; Tel: +48 12 6205580.

A library of 27 novel amide derivatives of annelated xanthines was designed and synthesized. The new compounds represent 1,3-dipropyl- and 1,3-dibutyl-pyrimido[2,1-]purinedione-9-ethylphenoxy derivatives including a CHCONH linker between the (CH)-amino group and the phenoxy moiety. A synthetic strategy to obtain the final products was developed involving solvent-free microwave irradiation. The new compounds were evaluated for their adenosine receptor (AR) affinities. The most potent derivatives contained a terminal tertiary amino function. Compounds with nanomolar AR affinities and at the same time high water-solubility were obtained (A ( = 24-605 nM), A ( = 242-1250 nM), A ( = 66-911 nM) and A ( = 155-1000 nM)). 2-(4-(2-(1,3-Dibutyl-2,4-dioxo-1,2,3,4,7,8-hexahydropyrimido[2,1-]purin-9(6)-yl)ethyl)phenoxy)--(3-(diethylamino)propyl)acetamide () and the corresponding -(2-(pyrrolidin-1-yl)ethyl)acetamide () were found to be the most potent antagonists of the present series. While showed CYP inhibition and moderate metabolic stability, was found to possess suitable properties for applications. In an attempt to explain the affinity data for the synthesized compounds, molecular modeling and docking studies were performed using homology models of A and A adenosine receptors. The potent compound was used as an example for discussion of the possible ligand-protein interactions. Moreover, the compounds showed high water-solubility indicating that the approach of introducing a basic side chain was successful for the class of generally poorly soluble AR antagonists.
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http://dx.doi.org/10.1039/c8md00070kDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6071793PMC
June 2018

Radiosynthesis and in vivo evaluation of a fluorine-18 labeled pyrazine based radioligand for PET imaging of the adenosine A receptor.

Bioorg Med Chem 2018 09 29;26(16):4650-4663. Epub 2018 Jul 29.

Helmholtz-Zentrum Dresden-Rossendorf, Institute of Radiopharmaceutical Cancer Research, Department of Neuroradiopharmaceuticals, Leipzig, Germany. Electronic address:

On the basis of a pyrazine core structure, three new adenosine A receptor ligands (7a-c) were synthesized containing a 2-fluoropyridine moiety suitable for F-labeling. Compound 7a was docked into a homology model of the A receptor based on X-ray structures of the related A receptor, and its interactions with the adenosine binding site were rationalized. Binding affinity data were determined at the four human adenosine receptor subtypes. Despite a rather low selectivity regarding the A receptor, 7a was radiolabeled as the most suitable candidate (K(A) = 4.24 nM) in order to perform in vivo studies in mice with the aim to estimate fundamental pharmacokinetic characteristics of the compound class. Organ distribution studies and a single PET study demonstrated brain uptake of [F]7a with a standardized uptake value (SUV) of ≈1 at 5 min post injection followed by a fast wash out. Metabolism studies of [F]7a in mice revealed the formation of a blood-brain barrier penetrable radiometabolite, which could be structurally identified. The results of this study provide an important basis for the design of new derivatives with improved binding properties and metabolic stability in vivo.
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http://dx.doi.org/10.1016/j.bmc.2018.07.045DOI Listing
September 2018

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

Front Chem 2018 26;6:206. Epub 2018 Jun 26.

PharmaCenter Bonn, Pharmaceutical Institute, Pharmaceutical Chemistry I, University of Bonn, Bonn, Germany.

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- ]purinediones with the aim to obtain multi-target drugs that block human A and A adenosine receptors (ARs) and monoaminoxidase B (MAO-B). 1,3-Diethyl-substituted derivatives showed high affinity for A ARs, e.g., (PSB-18339, 8--bromobenzyl-substituted) displayed a K value of 13.6 nM combined with high selectivity. 1-Ethyl-3-propargyl-substituted derivatives exhibited increased A AR affinity. The 8-phenethyl derivative was selective for the A AR (K 149 nM), while the corresponding 8-benzyl-substituted compound (PSB-1869) blocked A and A ARs with equal potency (K A, 180 nM; A, 282 nM). The 1-ethyl-3-methyl-substituted derivative (PSB-18405) bearing a -dichlorobenzyl residue at N8 blocked all three targets, A ARs (K 396 nM), A ARs (K 1,620 nM), and MAO-B (IC 106 nM) with high selectivity vs. the other subtypes (A and A 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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http://dx.doi.org/10.3389/fchem.2018.00206DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6028563PMC
June 2018

Tritium-labeled agonists as tools for studying adenosine A receptors.

Purinergic Signal 2018 09 11;14(3):223-233. Epub 2018 May 11.

PharmaCenter Bonn, Pharmaceutical Institute, Pharmaceutical Chemistry I, An der Immenburg 4, 53121, Bonn, Germany.

A selective agonist radioligand for A adenosine receptors (AARs) is currently not available. Such a tool would be useful for labeling the active conformation of the receptors. Therefore, we prepared BAY 60-6583, a potent and functionally selective AAR (partial) agonist, in a tritium-labeled form. Despite extensive efforts, however, we have not been able to establish a radioligand binding assay using [H]BAY 60-6583. This is probably due to its high non-specific binding and its moderate affinity, which had previously been overestimated based on functional data. As an alternative, we evaluated the non-selective AAR agonist [H]NECA for its potential to label AARs. [H]NECA showed specific, saturable, and reversible binding to membrane preparations of Chinese hamster ovary (CHO) or human embryonic kidney (HEK) cells stably expressing human, rat, or mouse AARs. In competition binding experiments, the AR agonists 2-chloroadenosine (CADO) and NECA displayed significantly higher affinity when tested versus [H]NECA than versus the A-antagonist radioligand [H]PSB-603 while structurally diverse AR antagonists showed the opposite effects. Although BAY 60-6583 is an AAR agonist, it displayed higher affinity versus [H]PSB-603 than versus [H]NECA. These results indicate that nucleoside and non-nucleoside agonists are binding to very different conformations of the AAR. In conclusion, [H]NECA is currently the only useful radioligand for determining the affinity of ligands for an active AAR conformation.
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http://dx.doi.org/10.1007/s11302-018-9608-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6107469PMC
September 2018

Adenosine A receptor ligand recognition and signaling is blocked by A receptors.

Oncotarget 2018 Mar 6;9(17):13593-13611. Epub 2018 Feb 6.

PharmaCenter Bonn, Pharmaceutical Institute, Pharmaceutical Chemistry I, University of Bonn, Bonn, Germany.

The adenosine receptor (AR) subtypes A and A are rhodopsin-like G protein-coupled receptors whose expression is highly regulated under pathological, e.g. hypoxic, ischemic and inflammatory conditions. Both receptors play important roles in inflammatory and neurodegenerative diseases, are blocked by caffeine, and have now become major drug targets in immuno-oncology. By Förster resonance energy transfer (FRET), bioluminescence resonance energy transfer (BRET), bimolecular fluorescence complementation (BiFC) and proximity ligation assays (PLA) we demonstrated A-AAR heteromeric complex formation. Moreover we observed a dramatically altered pharmacology of the AAR when co-expressed with the AAR (A ≥ A) in recombinant as well as in native cells. In the presence of AARs, A-selective ligands lost high affinity binding to AARs and displayed strongly reduced potency in cAMP accumulation and dynamic mass redistribution (DMR) assays. These results have major implications for the use of AAR ligands as drugs as they will fail to modulate the receptor in an A-A heteromer context. Accordingly, A-AAR heteromers represent novel pharmacological targets.
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http://dx.doi.org/10.18632/oncotarget.24423DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5862601PMC
March 2018

Understanding the Role of Adenosine A2AR Heteroreceptor Complexes in Neurodegeneration and Neuroinflammation.

Front Neurosci 2018 6;12:43. Epub 2018 Feb 6.

Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden.

Adenosine is a nucleoside mainly formed by degradation of ATP, located intracellularly or extracellularly, and acts as a neuromodulator. It operates as a volume transmission signal through diffusion and flow in the extracellular space to modulate the activity of both glial cells and neurons. The effects of adenosine are mediated via four adenosine receptor subtypes: A1R, A2AR, A2BR, A3R. The A2AR has a wide-spread distribution but it is especially enriched in the ventral and dorsal striatum where it is mainly located in the striato-pallidal GABA neurons at a synaptic and extrasynaptic location. A number of A2AR heteroreceptor complexes exist in the striatum. The existence of A2AR-D2R heteroreceptor complexes with antagonistic A2AR-D2R interactions in the striato-pallidal GABA neurons is well-known with A2AR activation inhibiting Gi/o mediated signaling of D2Rs. A2AR-mGluR5 heteroreceptor complexes were also found in with synergistic receptor-receptor interactions enhancing the inhibition of the D2R protomer signaling. They are located mainly in extrasynaptic regions of the striato-pallidal GABA neurons. Results recently demonstrated the existence of brain A2AR-A2BR heteroreceptor complexes, in which A2BR protomer constitutively inhibited the function of the A2AR protomer. These adenosine A2AR heteroreceptor complexes may modulate alpha-synuclein aggregation and toxicity through postulated bidirectional direct interactions leading to marked increases in A2AR signaling both in nerve cells and microglia. It is of high interest that formation of A2AR-A2ABR heteroreceptor complexes provides a brake on A2AR recognition and signaling opening up a novel strategy for treatment of A2AR mediated neurodegeneration.
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http://dx.doi.org/10.3389/fnins.2018.00043DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5808169PMC
February 2018

Adenosine A receptor agonists with potent antiplatelet activity.

Platelets 2018 May 15;29(3):292-300. Epub 2017 May 15.

d PharmaCenter Bonn , Pharmaceutical Institute, Pharmaceutical Chemistry I, University of Bonn , Bonn , Germany.

Selected adenosine A receptor agonists (PSB-15826, PSB-12404, and PSB-16301) have been evaluated as new antiplatelet agents. In addition, radioligand-binding studies and receptor-docking experiments were performed in order to explain their differential biological effects on a molecular level. Among the tested adenosine derivatives, PSB-15826 was the most potent compound to inhibit platelet aggregation (EC 0.32 ± 0.05 µmol/L) and platelet P-selectin cell-surface localization (EC 0.062 ± 0.2 µmol/L), and to increase intraplatelets cAMP levels (EC 0.24 ± 0.01 µmol/L). The compound was more active than CGS21680 (EC 0.97±0.07 µmol/L) and equipotent to NECA (EC 0.31 ± 0.05 µmol/L) in platelet aggregation induced by ADP. In contrast to the results from cAMP assays, K values determined in radioligand-binding studies were not predictive of the A agonists' antiplatelet activity. Docking studies revealed the key molecular determinants of this new family of adenosine A receptor agonists: differences in activities are related to π-stacking interactions between the ligands and the residue His264 in the extracellular loop of the adenosine A receptor which may result in increased residence times. In conclusion, these results provide an improved understanding of the requirements of antiplatelet adenosine A receptor agonists.
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http://dx.doi.org/10.1080/09537104.2017.1306043DOI Listing
May 2018

Nanodiscs for INPHARMA NMR Characterization of GPCRs: Ligand Binding to the Human A2A Adenosine Receptor.

Angew Chem Int Ed Engl 2017 05 21;56(21):5750-5754. Epub 2017 Apr 21.

Institute of Pharmacy, Eberhard Karls Universität Tübingen, Auf der Morgenstelle 8, 72076, Tübingen, Germany.

G-protein-coupled-receptors (GPCRs) are of fundamental importance for signal transduction through cell membranes. This makes them important drug targets, but structure-based drug design (SBDD) is still hampered by the limitations for structure determination of unmodified GPCRs. We show that the interligand NOEs for pharmacophore mapping (INPHARMA) method can provide valuable information on ligand poses inside the binding site of the unmodified human A adenosine receptor reconstituted in nanodiscs. By comparing experimental INPHARMA spectra with back-calculated spectra based on ligand poses obtained from molecular dynamics simulations, a complex structure for A R with the low-affinity ligand 3-pyrrolidin-1-ylquinoxalin-2-amine was determined based on the X-ray structure of ligand ZM-241,358 in complex with a modified A R.
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http://dx.doi.org/10.1002/anie.201612547DOI Listing
May 2017

Characterization of P2X4 receptor agonists and antagonists by calcium influx and radioligand binding studies.

Biochem Pharmacol 2017 Feb 17;125:41-54. Epub 2016 Nov 17.

PharmaCenter Bonn, Pharmaceutical Institute, Pharmaceutical Chemistry I, University of Bonn, An der Immenburg 4, D-53121 Bonn, Germany. Electronic address:

Antagonists for ATP-activated P2X4 ion channel receptors are currently in the focus as novel drug targets, in particular for the treatment of neuropathic and inflammatory pain. We stably expressed the human, rat and mouse P2X4 receptors in 1321N1 astrocytoma cells, which is devoid of functional nucleotide receptors, by retroviral transfection, and established monoclonal cell lines. Calcium flux assay conditions were optimized for high-throughput screening resulting in a Z'-factor of >0.8. The application of ready-to-use frozen cells did not negatively affect the results of the calcium assays, which is of great advantage for the screening of compound libraries. Species differences were observed, the rat P2X4 receptor being particularly insensitive to many ATP derivatives. Membrane preparations of the cell lines showed high levels of specific [S]ATPγS binding with low nonspecific binding (<5% of total binding), while non-transfected cells were devoid of specific binding sites for the radioligand. Conditions were employed which allow binding studies to be performed at room temperature. While a variety of nucleotide-derived agonists and the antagonist TNP-ATP displaced [S]ATPγS from its binding site at human P2X4 receptors, the non-nucleotidic antagonists paroxetine and 5-BDBD did not compete with radioligand binding and were therefore characterized as allosteric antagonists. Homology modeling was applied to find an explanation for the observed species differences.
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http://dx.doi.org/10.1016/j.bcp.2016.11.016DOI Listing
February 2017

8-Substituted 1,3-dimethyltetrahydropyrazino[2,1-f]purinediones: Water-soluble adenosine receptor antagonists and monoamine oxidase B inhibitors.

Bioorg Med Chem 2016 11 3;24(21):5462-5480. Epub 2016 Sep 3.

PharmaCenter Bonn, Pharmaceutical Institute, Pharmaceutical Chemistry I, University of Bonn, An der Immenburg 4, 53121 Bonn, Germany. Electronic address:

Multitarget approaches, i.e., addressing two or more targets simultaneously with a therapeutic agent, are hypothesized to offer additive therapeutic benefit for the treatment of neurodegenerative diseases. Validated targets for the treatment of Parkinson's disease are, among others, the A adenosine receptor (AR) and the enzyme monoamine oxidase B (MAO-B). Additional blockade of brain A ARs may also be beneficial. We recently described 8-benzyl-substituted tetrahydropyrazino[2,1-f]purinediones as a new lead structure for the development of such multi-target drugs. We have now designed a new series of tetrahydropyrazino[2,1-f]purinediones to extensively explore their structure-activity-relationships. Several compounds blocked human and rat A and AARs at similar concentrations representing dual A/A antagonists with high selectivity versus the other AR subtypes. Among the best dual A/AAR antagonists were 8-(3-(4-chlorophenyl)propyl)-1,3-dimethyl-6,7,8,9-tetrahydropyrazino[2,1-f]purine-2,4(1H,3H)-dione (41, K human A: 65.5nM, A: 230nM; K rat A: 352nM, A: 316nM) and 1,3-dimethyl-8-((2-(thiophen-2-yl)thiazol-4-yl)methyl)-6,7,8,9-tetrahydropyrazino[2,1-f]purine-2,4(1H,3H)-dione (57, K human A: 642nM, A: 203nM; K rat A: 166nM, A: 121nM). Compound 57 was found to be well water-soluble (0.7mg/mL) at a physiological pH value of 7.4. One of the new compounds showed triple-target inhibition: (R)-1,3-dimethyl-8-(2,1,3,4-tetrahydronaphthalen-1-yl)-6,7,8,9-tetrahydropyrazino[2,1-f]purine-2,4(1H,3H)-dione (49) was about equipotent at A and AARs and at MAO-B (K human A: 393nM, human A: 595nM, IC human MAO-B: 210nM) thus allowing future in vivo explorations of the intended multi-target approach.
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http://dx.doi.org/10.1016/j.bmc.2016.09.003DOI Listing
November 2016

Modeling ligand recognition at the P2Y12 receptor in light of X-ray structural information.

J Comput Aided Mol Des 2015 Aug 21;29(8):737-56. Epub 2015 Jul 21.

Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bldg. 8A, Rm. B1A-19, LBC, NIH, NIDDK, Bethesda, MD, 20892-0810, USA.

The G protein-coupled P2Y12 receptor (P2Y12R) is an important antithrombotic target and of great interest for pharmaceutical discovery. Its recently solved, highly divergent crystallographic structures in complex either with nucleotides (full or partial agonist) or with a nonnucleotide antagonist raise the question of which structure is more useful to understand ligand recognition. Therefore, we performed extensive molecular modeling studies based on these structures and mutagenesis, to predict the binding modes of major classes of P2Y12R ligands previously reported. Various nucleotide derivatives docked readily to the agonist-bound P2Y12R, but uncharged nucleotide-like antagonist ticagrelor required a hybrid receptor resembling the agonist-bound P2Y12R except for the top portion of TM6. Supervised molecular dynamics (SuMD) of ticagrelor binding indicated interactions with the extracellular regions of P2Y12R, defining possible meta-binding sites. Ureas, sulfonylureas, sulfonamides, anthraquinones and glutamic acid piperazines docked readily to the antagonist-bound P2Y12R. Docking dinucleotides at both agonist- and antagonist-bound structures suggested interactions with two P2Y12R pockets. Thus, our structure-based approach consistently rationalized the main structure-activity relationships within each ligand class, giving useful information for designing improved ligands.
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http://dx.doi.org/10.1007/s10822-015-9858-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4536181PMC
August 2015

Selectivity is species-dependent: Characterization of standard agonists and antagonists at human, rat, and mouse adenosine receptors.

Purinergic Signal 2015 Sep 1;11(3):389-407. Epub 2015 Jul 1.

Pharma Center Bonn, Pharmaceutical Institute, Pharmaceutical Chemistry I, University of Bonn, An der Immenburg 4, D-53121, Bonn, Germany,

Adenosine receptors (ARs) have emerged as new drug targets. The majority of data on affinity/potency and selectivity of AR ligands described in the literature has been obtained for the human species. However, preclinical studies are mostly performed in mouse or rat, and standard AR agonists and antagonists are frequently used for studies in rodents without knowing their selectivity in the investigated species. In the present study, we selected a set of frequently used standard AR ligands, 8 agonists and 16 antagonists, and investigated them in radioligand binding studies at all four AR subtypes, A1, A2A, A2B, and A3, of three species, human, rat, and mouse. Recommended, selective agonists include CCPA (for A1AR of rat and mouse), CGS-21680 (for A2A AR of rat), and Cl-IB-MECA (for A3AR of all three species). The functionally selective partial A2B agonist BAY60-6583 was found to additionally bind to A1 and A3AR and act as an antagonist at both receptor subtypes. The antagonists PSB-36 (A1), preladenant (A2A), and PSB-603 (A2B) displayed high selectivity in all three investigated species. MRS-1523 acts as a selective A3AR antagonist in human and rat, but is only moderately selective in mouse. The comprehensive data presented herein provide a solid basis for selecting suitable AR ligands for biological studies.
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http://dx.doi.org/10.1007/s11302-015-9460-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4529847PMC
September 2015

Indazole- and indole-5-carboxamides: selective and reversible monoamine oxidase B inhibitors with subnanomolar potency.

J Med Chem 2014 Aug 16;57(15):6679-703. Epub 2014 Jul 16.

Pharmaceutical Institute, Pharmaceutical Chemistry I, PharmaCenter Bonn, University of Bonn , An der Immenburg 4, D-53121 Bonn, Germany.

Indazole- and indole-carboxamides were discovered as highly potent, selective, competitive, and reversible inhibitors of monoamine oxidase B (MAO-B). The compounds are easily accessible by standard synthetic procedures with high overall yields. The most potent derivatives were N-(3,4-dichlorophenyl)-1-methyl-1H-indazole-5-carboxamide (38a, PSB-1491, IC50 human MAO-B 0.386 nM, >25000-fold selective versus MAO-A) and N-(3,4-dichlorophenyl)-1H-indole-5-carboxamide (53, PSB-1410, IC50 human MAO-B 0.227 nM, >5700-fold selective versus MAO-A). Replacement of the carboxamide linker with a methanimine spacer leading to (E)-N-(3,4-dichlorophenyl)-1-(1H-indazol-5-yl)methanimine (58) represents a further novel class of highly potent and selective MAO-B inhibitors (IC50 human MAO-B 0.612 nM, >16000-fold selective versus MAO-A). In N-(3,4-difluorophenyl-1H-indazole-5-carboxamide (30, PSB-1434, IC50 human MAO-B 1.59 nM, selectivity versus MAO-A>6000-fold), high potency and selectivity are optimally combined with superior physicochemical properties. Computational docking studies provided insights into the inhibitors' interaction with the enzyme binding site and a rationale for their high potency despite their small molecular size.
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http://dx.doi.org/10.1021/jm500729aDOI Listing
August 2014

8-Benzyltetrahydropyrazino[2,1-f]purinediones: water-soluble tricyclic xanthine derivatives as multitarget drugs for neurodegenerative diseases.

ChemMedChem 2014 Aug 9;9(8):1704-24. Epub 2014 May 9.

Pharmaceutical Chemistry I, Pharmaceutical Institute, PharmaCenter Bonn, University of Bonn, An der Immenburg 4, 53121 Bonn (Germany); Faculty for Chemistry and Chemical Biology TU Dortmund, Otto-Hahn-Straße 6, 44227 Dortmund (Germany).

8-Benzyl-substituted tetrahydropyrazino[2,1-f]purinediones were designed as tricyclic xanthine derivatives containing a basic nitrogen atom in the tetrahydropyrazine ring to improve water solubility. A library of 69 derivatives was prepared and evaluated in radioligand binding studies at adenosine receptor (AR) subtypes and for their ability to inhibit monoamine oxidases (MAO). Potent dual-target-directed A1 /A2A adenosine receptor antagonists were identified. Several compounds showed triple-target inhibition; one of the best compounds was 8-(2,4-dichloro-5-fluorobenzyl)-1,3-dimethyl-6,7,8,9-tetrahydropyrazino[2,1-f]purine-2,4(1H,3H)-dione (72) (human AR: Ki  A1 217 nM, A2A 233 nM; IC50 MAO-B: 508 nM). Dichlorinated compound 36 [8-(3,4-dichlorobenzyl)-1,3-dimethyl-6,7,8,9-tetrahydropyrazino[2,1-f]purine-2,4(1H,3H)-dione] was found to be the best triple-target drug in rat (Ki  A1 351 nM, A2A 322 nm; IC50 MAO-B: 260 nM), and may serve as a useful tool for preclinical proof-of-principle studies. Compounds that act at multiple targets relevant for symptomatic as well as disease-modifying treatment of neurodegenerative diseases are expected to show advantages over single-target therapeutics.
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http://dx.doi.org/10.1002/cmdc.201402082DOI Listing
August 2014

BAY60-6583 acts as a partial agonist at adenosine A2B receptors.

J Pharmacol Exp Ther 2014 Jun 14;349(3):427-36. Epub 2014 Mar 14.

PharmaCenter Bonn, Pharmaceutical Institute, Pharmaceutical Chemistry I, University of Bonn, Bonn, Germany.

BAY60-6583 [2-({6-amino-3,5-dicyano-4-[4-(cyclopropylmethoxy)phenyl]pyridin-2-yl}sulfanyl)acetamide] is the most potent and selective adenosine A2B receptor (A2B AR) agonist known to date. Therefore, it has been widely used for in vitro and in vivo experiments. In the present study, we investigated the binding and functional properties of BAY60-6583 in various native and recombinant cell lines with different A2B AR expression levels. In cAMP accumulation and calcium mobilization assays, BAY60-6583 was found to be significantly less efficacious than adenosine or the adenosine derivative NECA. When it was tested in human embryonic kidney (HEK)293 cells, its efficacy correlated with the A2B expression level of the cells. In Jurkat T cells, BAY60-6583 antagonized the agonistic effect of NECA and adenosine as determined in cAMP accumulation assays. On the basis of these results, we conclude that BAY60-6583 acts as a partial agonist at adenosine A2B receptors. At high levels of the physiologic agonist adenosine, BAY60-6583 may act as an antagonist and block the effects of adenosine at A2B receptors. This has to be considered when applying the A2B-selective "agonist" BAY60-6583 in pharmacological studies, and previous research results may have to be reinterpreted.
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http://dx.doi.org/10.1124/jpet.113.210849DOI Listing
June 2014

Alkynyl-coumarinyl ethers as MAO-B inhibitors.

Bioorg Med Chem 2014 Mar 8;22(6):1916-28. Epub 2014 Feb 8.

Pharmaceutical Institute, Pharmaceutical Chemistry I, University of Bonn, An der Immenburg 4, D-53121 Bonn, Germany. Electronic address:

In this study, alkynyl-coumarinyl ethers were developed as inhibitors of human monoamine oxidase B (MAO-B). A series of 31 new, ether-connected coumarin derivatives was synthesized via hydroxycoumarins, whose phenolic group at position 6, 7 or 8 was converted by means of the Mitsunobu reaction. The majority of the final products were produced from primary alcohols with a terminal alkyne group. The inhibitors were optimized with respect to the structure of the alkynyloxy chain and its position at the fused benzene ring as well as the residue at position 3 of the pyran-2H-one part. A hex-5-ynyloxy chain at position 7 was found to be particular advantageous. Among the 7-hex-5-ynyloxy-coumarins, the 3-methoxycarbonyl derivative 36 was characterized as a dual-acting inhibitor with IC₅₀ values of less than 10 nM towards MAO-A and MAO-B, and the 3-(4-methoxy)phenyl derivative 44 was shown to combine strong anti-MAO-B potency (IC₅₀=3.0 nM) and selectivity for MAO-B over MAO-A (selectivity >3400-fold).
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http://dx.doi.org/10.1016/j.bmc.2014.01.046DOI Listing
March 2014

Carbamazepine derivatives with P2X4 receptor-blocking activity.

Bioorg Med Chem 2014 Feb 25;22(3):1077-88. Epub 2013 Dec 25.

PharmaCenter Bonn, Pharmaceutical Institute, Pharmaceutical Chemistry I, University of Bonn, An der Immenburg 4, D-53121 Bonn, Germany. Electronic address:

Antagonists for the P2 receptor subtype P2X4, an ATP-activated cation channel receptor, have potential as novel drugs for the treatment of neuropathic pain and other inflammatory diseases. In the present study, a series of 47 carbamazepine derivatives including 32 novel compounds were designed, synthesized, and evaluated as P2X4 receptor antagonists. Their potency to inhibit ATP-induced calcium influx in 1321N1 astrocytoma cells stably transfected with the human P2X4 receptor was determined. Additionally, species selectivity (human, rat, mouse) and receptor subtype selectivity (P2X4 vs P2X1, 2, 3, 7) were investigated for selected derivatives. The most potent compound of the present series, which exhibited an allosteric mechanism of P2X4 inhibition, was N,N-diisopropyl-5H-dibenz[b,f]azepine-5-carboxamide (34, IC50 of 3.44μM). The present study extends the so far very limited knowledge on structure-activity relationships of P2X4 receptor antagonists.
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http://dx.doi.org/10.1016/j.bmc.2013.12.035DOI Listing
February 2014

Dual targeting of adenosine A(2A) receptors and monoamine oxidase B by 4H-3,1-benzothiazin-4-ones.

J Med Chem 2013 Jun 30;56(11):4580-96. Epub 2013 May 30.

PharmaCenter Bonn, University of Bonn, Pharmaceutical Institute, Pharmaceutical Chemistry I, Bonn, Germany.

Blockade of A2A adenosine receptors (A2AARs) and inhibition of monoamine oxidase B (MAO-B) in the brain are considered attractive strategies for the treatment of neurodegenerative diseases such as Parkinson's disease (PD). In the present study, benzothiazinones, e.g., 2-(3-chlorophenoxy)-N-(4-oxo-4H-3,1-benzothiazin-2-yl)acetamide (13), were identified as a novel class of potent MAO-B inhibitors (IC50 human MAO-B: 1.63 nM). Benzothiazinones with large substituents in the 2-position, e.g., methoxycinnamoylamino, phenylbutyrylamino, or chlorobenzylpiperazinylbenzamido residues (14, 17, 27, and 28), showed high affinity and selectivity for A2AARs (Ki human A2AAR: 39.5-69.5 nM). By optimizing benzothiazinones for both targets, the first potent, dual-acting A2AAR/MAO-B inhibitors with a nonxanthine structure were developed. The best derivative was N-(4-oxo-4H-3,1-benzothiazin-2-yl)-4-phenylbutanamide (17, Ki human A2A, 39.5 nM; IC50 human MAO-B, 34.9 nM; selective versus other AR subtypes and MAO-A), which inhibited A2AAR-induced cAMP accumulation and showed competitive, reversible MAO-B inhibition. The new compounds may be useful tools for validating the A2AAR/MAO-B dual target approach in PD.
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http://dx.doi.org/10.1021/jm400336xDOI Listing
June 2013
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