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 - JOUR A1 - Jesaitis, A. J. A1 - Klotz, Karl-Norbert T1 - Cytoskeletal regulation of chemotactic receptors: Molecular complexation of N-formyl peptide receptors with G proteins and actin N2 - Signal transduction via receptors for N-formylmethionyl peptide chemoattractants (FPR) on human neutrophils is a highly regulated process. It involves direct interaction of receptors with heterotrimeric G-proteins and may be under thc control of cytoskeletal clemcnts. Evidencc exists suggesting that thc cytoskeleton and/or the membrane ske1eton determines the distribution of FPR in the plane of the plasma membrane, thus controlling FPR accessibility to different protcins in functionally distinct membrane domains. In desensitized cells, FPR are restricted to domains which are depleted of G proteins but enriched in cytoskeletal proteins such as actin and fodrin. Thus, the G protein signal transduction partners of FPR become inacccssible to the agonist-occupied receptor, preventing cell activation. We are investigating the molecular basis for the interaction of FPR with the membrane skeleton, and our results suggest that FPR, and possibly other receptors, may directly bind to cytoskeletal proteins such as actin. KW - Immunologie KW - chemotaxis KW - formyl peptides KW - receptors KW - actin KW - G proteins KW - cytoskeleton KW - membrane skeleton Y1 - 1993 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-79673 ER - TY - JOUR A1 - Gonzalez-Calero, G. A1 - Cubero, A. A1 - Klotz, Karl-Norbert T1 - Characterization and photoaffinity labeling of A1 adenosine receptors in coated visicles form bovine brain N2 - The antagonist (3 II ) DPCPX exhi bitcd a Kd of 0. 4 nM at coalcd vcsicles from bovine brain. Agonist compelition for ( 3 11) DPCPX bind in~ revcaled two affini ty slales for gonists. The pholoaffinity probe I25 I -AHPIA specifically labelled a band with a molecular weight of 35 Kd. KW - Pharmakologie Y1 - 1991 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-86004 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 - 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 - 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 -