TY - JOUR A1 - Spinaci, Andrea A1 - Lambertucci, Catia A1 - Buccioni, Michela A1 - Dal Ben, Diego A1 - Graiff, Claudia A1 - Barbalace, Maria Cristina A1 - Hrelia, Silvana A1 - Angeloni, Cristina A1 - Tayebati, Seyed Khosrow A1 - Ubaldi, Massimo A1 - Masi, Alessio A1 - Klotz, Karl-Norbert A1 - Volpini, Rosaria A1 - Marucci, Gabriella T1 - A\(_{2A}\) adenosine receptor antagonists: are triazolotriazine and purine scaffolds interchangeable? JF - Molecules N2 - The A\(_{2A}\) adenosine receptor (A\(_{2A}\)AR) is one of the four subtypes activated by nucleoside adenosine, and the molecules able to selectively counteract its action are attractive tools for neurodegenerative disorders. In order to find novel A\(_{2A}\)AR ligands, two series of compounds based on purine and triazolotriazine scaffolds were synthesized and tested at ARs. Compound 13 was also tested in an in vitro model of neuroinflammation. Some compounds were found to possess high affinity for A\(_{2A}\)AR, and it was observed that compound 13 exerted anti-inflammatory properties in microglial cells. Molecular modeling studies results were in good agreement with the binding affinity data and underlined that triazolotriazine and purine scaffolds are interchangeable only when 5- and 2-positions of the triazolotriazine moiety (corresponding to the purine 2- and 8-positions) are substituted. KW - A\(_{2A}\) adenosine receptor antagonist KW - purine derivatives KW - triazolotriazine derivatives KW - anti-Parkinson agents KW - anti-inflammatory agents KW - molecular modeling Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-270618 SN - 1420-3049 VL - 27 IS - 8 ER - TY - JOUR A1 - Vazquez-Rodriguez, Saleta A1 - Vilar, Santiago A1 - Kachler, Sonja A1 - Klotz, Karl-Norbert A1 - Uriarte, Eugenio A1 - Borges, Fernanda A1 - Matos, Maria João T1 - Adenosine receptor ligands: coumarin−chalcone hybrids as modulating agents on the activity of hARs JF - Molecules N2 - Adenosine receptors (ARs) play an important role in neurological and psychiatric disorders such as Alzheimer's disease, Parkinson's disease, epilepsy and schizophrenia. The different subtypes of ARs and the knowledge on their densities and status are important for understanding the mechanisms underlying the pathogenesis of diseases and for developing new therapeutics. Looking for new scaffolds for selective AR ligands, coumarin–chalcone hybrids were synthesized (compounds 1–8) and screened in radioligand binding (hA\(_1\), hA\(_{2A}\) and hA\(_3\)) and adenylyl cyclase (hA\(_{2B}\)) assays in order to evaluate their affinity for the four human AR subtypes (hARs). Coumarin–chalcone hybrid has been established as a new scaffold suitable for the development of potent and selective ligands for hA\(_1\) or hA\(_3\) subtypes. In general, hydroxy-substituted hybrids showed some affinity for the hA\(_1\), while the methoxy counterparts were selective for the hA\(_3\). The most potent hA\(_1\) ligand was compound 7 (K\(_i\) = 17.7 µM), whereas compound 4 was the most potent ligand for hA\(_3\) (K\(_i\) = 2.49 µM). In addition, docking studies with hA\(_1\) and hA\(_3\) homology models were established to analyze the structure–function relationships. Results showed that the different residues located on the protein binding pocket could play an important role in ligand selectivity. KW - coumarin KW - chalcone KW - neurodegenerative diseases KW - adenosine receptors KW - binding affinity KW - docking Y1 - 2020 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-213165 SN - 1420-3049 VL - 25 IS - 18 ER - TY - JOUR A1 - Tan, Aaron A1 - Babak, Maria V. A1 - Venkatesan, Gopalakrishnan A1 - Lim, Clarissa A1 - Klotz, Karl-Norbert A1 - Herr, Deron Raymond A1 - Cheong, Siew Lee A1 - Federico, Stephanie A1 - Spalluto, Giampiero A1 - Ong, Wei-Yi A1 - Chen, Yu Zong A1 - Loo, Jason Siau Ee A1 - Pastorin, Giorgia T1 - Design, Synthesis and Evaluation of New Indolylpyrimidylpiperazines for Gastrointestinal Cancer Therapy JF - Molecules N2 - Human A3 adenosine receptor hA3AR has been implicated in gastrointestinal cancer, where its cellular expression has been found increased, thus suggesting its potential as a molecular target for novel anticancer compounds. Observation made in our previous work indicated the importance of the carbonyl group of amide in the indolylpyrimidylpiperazine (IPP) for its human A2A adenosine receptor (hA2AAR) subtype binding selectivity over the other AR subtypes. Taking this observation into account, we structurally modified an indolylpyrimidylpiperazine (IPP) scaffold, 1 (a non-selective adenosine receptors’ ligand) into a modified IPP (mIPP) scaffold by switching the position of the carbonyl group, resulting in the formation of both ketone and tertiary amine groups in the new scaffold. Results showed that such modification diminished the A2A activity and instead conferred hA3AR agonistic activity. Among the new mIPP derivatives (3–6), compound 4 showed potential as a hA3AR partial agonist, with an Emax of 30% and EC50 of 2.89 ± 0.55 μM. In the cytotoxicity assays, compound 4 also exhibited higher cytotoxicity against both colorectal and liver cancer cells as compared to normal cells. Overall, this new series of compounds provide a promising starting point for further development of potent and selective hA3AR partial agonists for the treatment of gastrointestinal cancers. KW - gastrointestinal cancer KW - hA3AR KW - partial agonists KW - indolylpyrimidylpiperazines Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-193271 SN - 1420-3049 VL - 24 IS - 20 ER - TY - JOUR A1 - Federico, Stephanie A1 - Redenti, Sara A1 - Sturlese, Mattia A1 - Ciancetta, Antonella A1 - Kachler, Sonja A1 - Klotz, Karl-Norbert A1 - Cacciari, Barbara A1 - Moro, Stefano A1 - Spalluto, Giampiero T1 - The Influence of the 1-(3-Trifluoromethyl-Benzyl)-1H-Pyrazole-4-yl Moiety on the Adenosine Receptors Affinity Profile of Pyrazolo[4,3-e][1,2,4]Triazolo[1,5-c]Pyrimidine Derivatives JF - PLoS One N2 - A new series of pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidine (PTP) derivatives has been developed in order to explore their affinity and selectivity profile at the four adenosine receptor subtypes. In particular, the PTP scaffold was conjugated at the C2 position with the 1-(3-trifluoromethyl-benzyl)-1H-pyrazole, a group believed to confer potency and selectivity toward the human (h) A\(_{2B}\) adenosine receptor (AR) to the xanthine ligand 8-(1-(3-(trifluoromethyl) benzyl)-1H-pyrazol-4-yl)-1,3-dimethyl-1H-purine-2,6(3H, 7H)-dione (CVT 6975). Interestingly, the synthesized compounds turned out to be inactive at the hA\(_{2B}\) AR but they displayed affinity at the hA\(_3\) AR in the nanomolar range. The best compound of the series (6) shows both high affinity (hA\(_3\) AR K\(_i\) = 11 nM) and selectivity (A\(_1\)/A\(_3\) and A\(_{2A}\)/A\(_3\) > 9090; A\(_{2B}\)/A\(_3\) > 909) at the hA\(_3\) AR. To better rationalize these results, a molecular docking study on the four AR subtypes was performed for all the synthesized compounds. In addition, CTV 6975 and two close analogues have been subjected to the same molecular docking protocol to investigate the role of the 1-(3-trifluoromethyl-benzyl)-1H-pyrazole on the binding at the four ARs. KW - drug KW - human A(3) KW - protein-coupled receptors KW - classification KW - subtypes KW - potent KW - antagonists KW - mast cells KW - targets KW - A(2B) receptors KW - international union Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-137133 VL - 10 IS - 12 ER - TY - JOUR A1 - Lohse, Martin J. A1 - Klotz, Karl-Norbert A1 - Salzer, Manfred J. A1 - Schwabe, Ulrich T1 - Adenosine regulates the \(Ca^{2+} \) sensitivity of mast cell mediator release : (histamine secretion/inositol phosphates/calcium) JF - Proceedings of the National Academy of Sciences of the United States of America N2 - Mast cells release histamine and other mediators of allergy in response to stimulation of their IgE receptors. This release is generally thought to be mediated by an elevation of cytosolic \(Ca^{2+}\). Recent evidence suggests that there might be factors that modulate the coupling between \(Ca^{2+}\) levels and mediator release. The present report identifies adenosine as one such modulator. Adenosine and several of its metabolically stable analogues were shown to enhance histamine release from rat peritoneal mast cells in response to stimuli such as concanavalin A. Metabolizing endogenous adenosine with adenosine deaminase dampened the response to stimuli, whereas trapping endogenous adenosine inside mast cells with nucleoside-transport inhibitors markedly enhanced stimulated histamine release. The metabolically stable adenosine analogue 5' -(N-ethylcarboxamido)adenosine (NECA) did not affect the initial steps in the sequence from IgE-receptor activation to mediator release, which are generation of inositol trisphosphate and increase of cytosolic \(Ca^{2+}\). However, NECA did enhance the release induced in ATP-permeabilized cells by exogenous \(Ca^{2+}\), but it had no effect on the release induced by phorbol esters. These data suggest that adenosine sensitizes mediator release by a mechanism regulating stimulus-secretion coupling at a step distal to receptor activation and second-messenger generation. Y1 - 1988 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-127883 VL - 85 ER - TY - JOUR A1 - Ott, Ilka A1 - Lohse, Martin J. A1 - Klotz, Karl-Norbert A1 - Vogt-Moykopf, Ingolf A1 - Schwabe, Ulrich T1 - Effects of Adenosine on Histamine Release from Human Lung Fragments JF - International Archives of Allergy and Immunology N2 - The actions of adenosine on histamine release of human lung fragments were investigated. Histamine release was stimulated either with the calcium ionophore A 23187 orwith concanavalin A. Adenosine and its analogue 5'-N-ethylcarboxamidoadenosine alone had no significant effect on basal release or on the release elicited by A 23187 or concanavalin A. However, in the presence of the adenosine receptor antagonist 8-[4-[[[[(2-aminoethyl)amino]-carbonyl] methyloxy]-phenyl]-1,3-dipropylaxanthine (XAC), which itself did not affect the release, adenosine increased the stimulated histamine release. On the other hand, in the presence of the nucleoside transport inhibitor S-(p-nitrobenzyl)-6-thioninosine (NBTI), adenosine caused a reduction in stimulated histamine release. NBTI itself caused a stimulation of release. Thus, a stimulatory effect of adenosine was seen in the presence ofXAC, whereas an inhibitory effect was unmasked by NBTI. From these data it is concluded that adenosine exerts two opposing effects on histamine release in the human lung which neutralize each other: it inhibits release via a si te antagonized by XAC, which presumably represents an A2 adenosine receptor, and it stimulates release via a mechanism that is blocked by NBTI, suggesting that adenosine needs to reach the interior of cells to exert this effect. The slight stimulatory effect of NBTI alone demonstrates that trapping intracellularly formed adenosine inside mast cells leads to sufficient concentrations of adenosine to stimulate histamine release. These findings suggest an important bimodal role of adenosine in regulating histamine release in the human lung. KW - mast cells KW - adenosine KW - histamine release KW - human lung Y1 - 1982 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-127877 VL - 98 ER - TY - JOUR A1 - Meier, Friedegund A1 - Gross, Eva A1 - Klotz, Karl-Norbert A1 - Ruzicka, Thomas T1 - Leukotriene B4 receptors on neutrophils in patients with psoriasis and atopic exzema N2 - Polymorphonuclear leukocyte (PMNL) infiltration is an important characteristic in psoriatic lesions. Elevated concentrations of the chemoattractant eicosanoid leukotriene B4 (L TB4) are present in psoriatic skin. Its chemotactic activity is mediated via high affinity receptors on PMNL. The goal of our work was to ascertain whether PMNL infiltration in psoriasis can be accounted for by functional abnormalities of the circulating PMNL due to alterations in the LTB4 receptor density or affinity (or both). No significant difference was found between patients with psoriasis, healthy controls and patients with another inflammatory dermatosis (atopic eczema) with regard to the binding parameters of LTB4 receptors on PMNL. Our findings suggest that PMNL accumulation in psoriatic skin may be the result of an excess of cutaneous hemoattractant rather than the increased readiness of psoriatic PMNL to migrate towards L TB4 due to altered LTB4 receptor density or affinity. KW - Dermatologie KW - Venerologie KW - Pharmakologie KW - Pharmazie KW - LTB4 receptor KW - neutrophils KW - psoriasis KW - atopic eczema Y1 - 1989 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-86265 ER - TY - CHAP A1 - Klotz, Karl-Norbert A1 - Keil, Roger A1 - Zimmer, Franz-Josef A1 - Schwabe, Ulrich T1 - Modulation of (§H) DPCPX binding to membrane-bound ans solubilized A1 adenosine receptors by guanine nucleotides N2 - No abstract available KW - Adenosinrezeptor Y1 - 1989 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-86153 ER - TY - CHAP A1 - Spielmann, W. S. A1 - Arend, L. J. A1 - Klotz, Karl-Norbert A1 - Schwabe, U. T1 - Adenosine control of the renal Collecting tubule: receptors and signaling N2 - No abstract available. KW - Adenosin Y1 - 1991 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-86129 ER - TY - CHAP A1 - Spielmann, W.-S. A1 - Arend, L. J. A1 - Klotz, Karl-Norbert A1 - Schwabe, U. T1 - Adenosine receptors and singnaling in the kidney N2 - No abstract available. KW - Adenosinrezeptor KW - Niere Y1 - 1990 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-86114 ER -