TY  - JOUR
A1  - Wilken, Anke
A1  - Klotz, Karl-Norbert
A1  - Tawfik-Schlieper, Hoda
A1  - Schwabe, Ulrich
T1  - Pharmacological characterization of the adenylate cyclase-coupled adenosine receptor in isolated guinea pig atrial myocytes
N2  - No abstract available.
KW  - Pharmakologie
Y1  - 1990
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-86061
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  - van Calker, D.
A1  - Steber, R.
A1  - Klotz, Karl-Norbert
A1  - Greil, W.
T1  - Carbamazepine distinguishes between adenosine receptors that mediate different second messenger responses
N2  - The mechanism of the therapeutic and prophylactic effects of carbamazepine (CBZ) in affective psychoses is unknown but may in part be related to the potent competitive interaction of CBZ with adenosine-binding sites in the brain. The antioonvulsant and sedative properties of CBZ are reminiscent of the effects evoked by adenosine-agonists and contrast sharply with the opposite aclions of adenosine-antagonists like caffeine. However. indirect evidence suggests an antagonist- rather than an agonist-like activity of CBZ at adenosi11e-receptors. We have used various model systems, in which adenosine receptor subtypes mediate different second messenger-responses, to investigate this apparent paradox. CBZ was found to antagonize the A\(_1\) receptor-mediated inhibition of cydic AMP accumulation in cultured astroblasts and in GH3-cells. Furthermore, CBZ also inhibits the adenosine-induced increase in the level of cyclic AMP in cultured astroblasts, which is mediated by low-affinity A\(_{2b}\)-receptors. ln contrast, CBZ does not block the inhibition elicited by adenosine-agonists of the agonist-induced increased formation of inositolphosphates in human neutrophils, which is mediated by high-affinity A\(_{2a}\)-receptors. The specific antagonism by CBZ of A\(_1\)- but not of high-affinity A\(_{2a}\)-receptors was further supported by binding experiments using rat brain membranes. These results suggest tbat the paradox of CBZ's antagonistic effects at adenosine-receptors might be at least partially reconciled by a selective antagonistic action of CBZ at A\(_1\)recertors but not at high-affinity A\(_{2a}\)-receptors.
KW  - Toxikologie
Y1  - 1991
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-60392
ER  - 
TY  - JOUR
A1  - Ukena, D.
A1  - Schirren, C. G.
A1  - Klotz, Karl-Norbert
A1  - Schwabe, U.
T1  - Evidence for an A\(_2\) adenosine receptor in guinea pig lung
N2  - Adenosine receptors in guinea pig lung were characterized by measurement of cyclic AMP formation and radioligand binding. 5'-N-Ethylcarboxamidoadenosine (NECA) increased cyclic AMP Ievels in lung slices about 4-fold over basal values with an EC\(_{50}\) of 0.32 \(\mu\)mol/l. N\(^6\) - R-(- )-Phenylisopropyladenosine (R-PIA) was 5-fold less potent than NECA. 5'-N-Methylcarboxamidoadenosine (MECA) and 2-chloroadenosine had EC\(_{50}\)-values of 0.29 and 2.6 \(\mu\)mol/l, whereas adenosine and inosine had no effect. The adenosine receptors in guinea pig Iung can therefore be classified as A\(_2\) receptors. Several xanthine derivatives antagonized the NECA-induced increase in cyclic AMP levels. 1,3-Diethyl-8-phenylxanthine (DPX; K\(_i\) 0.14 \(\mu\)mol/l) was the most potent analogue, followed by 8-phenyltheophylline (K\(_i\) 0.55 \(\mu\)mol/l), 3-isobutyl-1-methylxanthine (IBMX; K\(_i\) 2.9 \(\mu\)mol/l) and theophylline (K\(_i\) 8.1 \(\mu\)mol/l). In contrast, enprofylline (1 mmol/1) enhanced basal and NECA-stimulated cyclic AMP formation. In addition, we attempted to characterize these receptors in binding studies with [\(^3\)H]NECA. The K\(_D\) for [\(^3\)H] NECA was 0.25 \(\mu\)mol/l and the maximal number of binding sites was 12 pmol/mg protein. In competition experiments MECA (K\(_i\) 0.14 \(\mu\)mol/l) was the most potent inhibitor of [\(^3\)H] NECA binding, followed by NECA (K\(_i\) 0.19 \(\mu\)mol/l) and 2-chloroadenosine (K\(_i\) 1.4 \(\mu\)mol/l). These results correlate well with the EC\(_{50}\)- values for cyclic AMP formation in lung slices. However, the K\(_i\)-values of R-PIA and theophylline were 240 and 270 \(\mu\)mol/l, and DPX and 8-phenyltheophylline did not compete for [\(^3\)H]NECA binding sites. Therefore, a complete characterization of A\(_2\) adenosine receptors by [\(^3\)H] NECA binding was not achieved. In conclusion, our results show the presence of adenylate cyclase-coupled A\(_2\) adenosiile receptors in lung tissue which are antagonized by several xanthines.
KW  - Toxikologie
KW  - Adenosine receptors
KW  - Cyclic AMP
KW  - Lung
KW  - Theophylline
Y1  - 1985
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-60202
ER  - 
TY  - JOUR
A1  - Tawfik-Schlieper, H.
A1  - Klotz, Karl-Norbert
A1  - Kreye, V. A. W.
A1  - Schwabe, U.
T1  - Characterization of the K\(^+\)-channel-coupled adenosine receptor in guinea pig atria
N2  - In the present work we studied the pharmacological profile of adenosine receptors in guinea pig atria by investigating the effect of different adenosine analogues on 86Rb + -efflux from isolated left atria and on binding of the antagonist radioligand 8-cyclopentyl-1 ,3-[\(^3\)H]dipropylxanthine ([\(^3\)H]DPCPX) to atrial membrane preparations. The rate of \8^{86}\)Rb\(^+\) -effiux was increased twofold by the maximally effective concentrations of adenosine receptor agonists. The EC50-values for 2-chloro-N\(^6\)-cyclopentyladenosine (CCPA), R-N\(^6\)-phenylisopropyladenosine (R-PIA), 5'-Nethylcarboxamidoadenosine (NECA), and S-N\(^6\)-phenylisopropyladenosine (S-PIA) were 0.10, 0.14, 0.24 and 12.9 \(\mu\)M, respectively. DPCPX shifted the R-PIA concentration-response curve to the right in a concentration-dependent manner with a K\(_B\)-value of 8.1 nM, indicating competitive antagonism. [\(^3\)H]DPCPX showed a saturable binding to atrial membranes with a Bmax·value of 227 fmol/mg protein and a K\(_D\)-value of 1.3 nM. Competition experiments showed a similar potency for the three agonists CCPA, R-PIA and NECA. S-PIA is 200 times less potent than R-PIA. Our results suggest that the K\(^+\) channel-coupled adenosine receptor in guinea pig atria is of an A\(_1\) subtype.
KW  - Toxikologie
KW  - A1 Adenosine receptors
KW  - K + -channels
KW  - Atria
KW  - Radioligand binding - 86Rb + -efflux
Y1  - 1989
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-60333
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  - hA<sub>3</sub>AR
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  - 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  - 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  - 
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  - JOUR
A1  - Spielman, William S.
A1  - Klotz, Karl-Norbert
A1  - Arend, Lois J.
A1  - Olson, Barbara A.
A1  - LeVier, David G.
A1  - Schwabe, Ulrich
T1  - Characterization of adenosine A1 receptor in a cell line (28A) derived from the rabbit collecting tubule
N2  - We have previously reported that in several renal cell types, adenosine receptor agonists inhibit adenylyl cyclase and activate phospholipase C via a pertussis toxin-sensitive G protein. In the present study, in 28A cells, both uf these adenosine receptor-mediated responses were inhibited by 8-cyclopentyl-1,3-dipropylxanthine (DPCPX). a highly selective A1 adenosine receptor antagonist. The binding characteristics of the adenosine A 1 receptor in the 28A renal cell line were studied using the radiolabeled antagonist f:1H]DPCPX to determine whether two separate binding sites could account for these responses. Saturation binding of [: 1H]DPCPX to 28A cell membranes revealed a single class of A1 binding sites with an apparent Kd value of 1.4 nM and maximal binding capacity of 64 fmol/mg protein. Competition experiments with a variety of adenosine agonists gave biphasic displacement curves with a pharmacological profile characteristic of A1 receptors. Comparison of [: 1H]DPCPX competition binding data from 28A cell membranes with rabbit brain membranes, a tissue with well-characterized A1 receptors, reveals that the A 1 receptor population in 28A cells has similar agonist binding affinities to the receptor population in brain but has a considerably lower density. Addition of guanosine ;)' -triphosphate ( 100 ,uM) to 28A cell membranes caused the competition curves to shift from biphasic to monophasic. indicating that the A1 receptors exist in two interconvertible affinity states because of their coupling to G proteins. In the absence of evidence for subpopulations of the A1 receptor, it appears that in 28A cells. A single A1 receptor population. As defined by ligand binding characteristics, couples via one or more pertussis toxin-sensitive guanine nucleotide binding proteins to two different biological signaling mechanisms.
KW  - calcium
KW  - phosphoinositides
KW  - adenosine 3',5'-cyclic monophosphate
KW  - receptor binding
KW  - signal transduction
KW  - G proteins
Y1  - 1992
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-86083
ER  -