Rafehi, Muhammad

[["dc.bibliographiccitation.firstpage","3020-3038"],["dc.bibliographiccitation.issue","7"],["dc.bibliographiccitation.journal","Journal of Medicinal Chemistry"],["dc.bibliographiccitation.lastpage","3038"],["dc.bibliographiccitation.volume","60"],["dc.contributor.author","Rafehi, Muhammad"],["dc.contributor.author","Malik, Enas M"],["dc.contributor.author","Neumann, Alexander"],["dc.contributor.author","Abdelrahman, Aliaa"],["dc.contributor.author","Hanck, Theodor"],["dc.contributor.author","Namasivayam, Vigneshwaran"],["dc.contributor.author","Müller, Christa E"],["dc.contributor.author","Baqi, Younis"],["dc.date.accessioned","2020-10-22T08:51:30Z"],["dc.date.available","2020-10-22T08:51:30Z"],["dc.date.issued","2017"],["dc.description.abstract","P2Y4 is a Gq protein-coupled receptor activated by uridine-5'-triphosphate (UTP), which is widely expressed in the body, e.g., in intestine, heart, and brain. No selective P2Y4 receptor antagonist has been described so far. Therefore, we developed and optimized P2Y4 receptor antagonists based on an anthraquinone scaffold. Potency was assessed by a fluorescence-based assay measuring inhibition of UTP-induced intracellular calcium release in 1321N1 astrocytoma cells stably transfected with the human P2Y4 receptor. The most potent compound of the present series, sodium 1-amino-4-[4-(2,4-dimethylphenylthio)phenylamino]-9,10-dioxo-9,10-dihydroanthracene-2-sulfonate (PSB-16133, 61) exhibited an IC50 value of 233 nM, selectivity versus other P2Y receptor subtypes, and is thought to act as an allosteric antagonist. A receptor homology model was built and docking studies were performed to analyze ligand-receptor interactions. Compound 64 (PSB-1699, sodium 1-amino-4-[4-(3-pyridin-3-ylmethylthio)phenylamino]-9,10-dioxo-9,10-dihydroanthracene-2-sulfonate) represents the most selective P2Y4 receptor antagonist known to date. Compounds 61 and 64 are therefore anticipated to become useful tools for studying this scarcely investigated receptor."],["dc.identifier.doi","10.1021/acs.jmedchem.7b00030"],["dc.identifier.pmid","28306255"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/68021"],["dc.language.iso","en"],["dc.relation.eissn","1520-4804"],["dc.relation.issn","0022-2623"],["dc.title","Development of Potent and Selective Antagonists for the UTP-Activated P2Y4 Receptor"],["dc.type","journal_article"],["dc.type.internalPublication","no"],["dc.type.subtype","original_ja"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.firstpage","1898"],["dc.bibliographiccitation.issue","8"],["dc.bibliographiccitation.journal","British Journal of Pharmacology"],["dc.bibliographiccitation.lastpage","1916"],["dc.bibliographiccitation.volume","177"],["dc.contributor.author","Kuschak, Markus"],["dc.contributor.author","Namasivayam, Vigneshwaran"],["dc.contributor.author","Rafehi, Muhammad"],["dc.contributor.author","Voss, Jan H."],["dc.contributor.author","Garg, Jaspal"],["dc.contributor.author","Schlegel, Jonathan G."],["dc.contributor.author","Abdelrahman, Aliaa"],["dc.contributor.author","Kehraus, Stefan"],["dc.contributor.author","Reher, Raphael"],["dc.contributor.author","Küppers, Jim"],["dc.contributor.author","Sylvester, Katharina"],["dc.contributor.author","Hinz, Sonja"],["dc.contributor.author","Matthey, Michaela"],["dc.contributor.author","Wenzel, Daniela"],["dc.contributor.author","Fleischmann, Bernd K."],["dc.contributor.author","Pfeifer, Alexander"],["dc.contributor.author","Inoue, Asuka"],["dc.contributor.author","Gütschow, Michael"],["dc.contributor.author","König, Gabriele M."],["dc.contributor.author","Müller, Christa E."],["dc.date.accessioned","2020-09-16T14:34:46Z"],["dc.date.available","2020-09-16T14:34:46Z"],["dc.date.issued","2020"],["dc.description.abstract","G proteins are intracellular switches that transduce and amplify extracellular signals from GPCRs. The Gq 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. Gq inhibition may be an efficient therapeutic strategy constituting a new level of intervention. However, diagnostic tools and therapeutic drugs for Gq proteins are lacking."],["dc.identifier.doi","10.1111/bph.14960"],["dc.identifier.pmid","31881095"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/67698"],["dc.language.iso","en"],["dc.relation.eissn","1476-5381"],["dc.relation.issn","0007-1188"],["dc.relation.issn","1476-5381"],["dc.title","Cell‐permeable high‐affinity tracers for G q proteins provide structural insights, reveal distinct binding kinetics and identify small molecule inhibitors"],["dc.type","journal_article"],["dc.type.internalPublication","no"],["dc.type.subtype","original_ja"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.firstpage","89-103"],["dc.bibliographiccitation.issue","1"],["dc.bibliographiccitation.journal","Purinergic Signalling"],["dc.bibliographiccitation.lastpage","103"],["dc.bibliographiccitation.volume","13"],["dc.contributor.author","Rafehi, Muhammad"],["dc.contributor.author","Burbiel, Joachim C"],["dc.contributor.author","Attah, Isaac Y"],["dc.contributor.author","Abdelrahman, Aliaa"],["dc.contributor.author","Müller, Christa E"],["dc.date.accessioned","2020-10-22T08:51:21Z"],["dc.date.available","2020-10-22T08:51:21Z"],["dc.date.issued","2017"],["dc.description.abstract","The Gq protein-coupled, ATP- and UTP-activated P2Y2 receptor is a potential drug target for a range of different disorders, including tumor metastasis, inflammation, atherosclerosis, kidney disorders, and osteoporosis, but pharmacological studies are impeded by the limited availability of suitable antagonists. One of the most potent and selective antagonists is the thiouracil derivative AR-C118925. However, this compound was until recently not commercially available and little is known about its properties. We therefore developed an improved procedure for the synthesis of AR-C118925 and two derivatives to allow up-scaling and assessed their potency in calcium mobilization assays on the human and rat P2Y2 receptors recombinantly expressed in 1321N1 astrocytoma cells. The compound was further evaluated for inhibition of P2Y2 receptor-induced β-arrestin translocation. AR-C118925 behaved as a competitive antagonist with pA 2 values of 37.2 nM (calcium assay) and 51.3 nM (β-arrestin assay). Selectivity was assessed vs. related receptors including P2X, P2Y, and adenosine receptor subtypes, as well as ectonucleotidases. AR-C118925 showed at least 50-fold selectivity against the other investigated targets, except for the P2X1 and P2X3 receptors which were blocked by AR-C118925 at concentrations of about 1 μM. AR-C118925 is soluble in buffer at pH 7.4 (124 μM) and was found to be metabolically highly stable in human and mouse liver microsomes. In Caco2 cell experiments, the compound displayed moderate permeability indicating that it may show limited peroral bioavailability. AR-C118925 appears to be a useful pharmacological tool for in vitro and in vivo studies."],["dc.identifier.doi","10.1007/s11302-016-9542-3"],["dc.identifier.pmid","27766552"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/68020"],["dc.language.iso","en"],["dc.relation.eissn","1573-9546"],["dc.relation.issn","1573-9538"],["dc.title","Synthesis, characterization, and in vitro evaluation of the selective P2Y2 receptor antagonist AR-C118925"],["dc.type","journal_article"],["dc.type.internalPublication","no"],["dc.type.subtype","original_ja"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.firstpage","8136"],["dc.bibliographiccitation.issue","18"],["dc.bibliographiccitation.journal","Journal of Medicinal Chemistry"],["dc.bibliographiccitation.lastpage","8154"],["dc.bibliographiccitation.volume","61"],["dc.contributor.author","Baqi, Younis"],["dc.contributor.author","Pillaiyar, Thanigaimalai"],["dc.contributor.author","Abdelrahman, Aliaa"],["dc.contributor.author","Kaufmann, Olesja"],["dc.contributor.author","Alshaibani, Samer"],["dc.contributor.author","Rafehi, Muhammad"],["dc.contributor.author","Ghasimi, Saman"],["dc.contributor.author","Akkari, Rhalid"],["dc.contributor.author","Ritter, Kirsten"],["dc.contributor.author","Simon, Katharina"],["dc.contributor.author","Spinrath, Andreas"],["dc.contributor.author","Kostenis, Evi"],["dc.contributor.author","Zhao, Qiang"],["dc.contributor.author","Köse, Meryem"],["dc.contributor.author","Namasivayam, Vigneshwaran"],["dc.contributor.author","Müller, Christa E"],["dc.date.accessioned","2020-10-22T08:52:37Z"],["dc.date.available","2020-10-22T08:52:37Z"],["dc.date.issued","2018"],["dc.description.abstract","The orphan receptor GPR17 may be a novel drug target for inflammatory diseases. 3-(2-Carboxyethyl)-4,6-dichloro-1 H-indole-2-carboxylic acid (MDL29,951, 1) was previously identified as a moderately potent GPR17 agonist. In the present study, we investigated the structure-activity relationships (SARs) of 1. Substitution of the indole 1-, 5-, or 7-position was detrimental. Only small substituents were tolerated in the 4-position while the 6-position accommodated large lipophilic residues. Among the most potent compounds were 3-(2-carboxyethyl)-1 H-indole-2-carboxylic acid derivatives containing the following substituents: 6-phenoxy (26, PSB-1737, EC50 270 nM), 4-fluoro-6-bromo (33, PSB-18422, EC50 27.9 nM), 4-fluoro-6-iodo (35, PSB-18484, EC50 32.1 nM), and 4-chloro-6-hexyloxy (43, PSB-1767, EC50 67.0 nM). (3-(2-Carboxyethyl)-6-hexyloxy-1 H-indole-2-carboxylic acid (39, PSB-17183, EC50 115 nM) behaved as a partial agonist. Selected potent compounds tested at human P2Y receptor subtypes showed high selectivity for GPR17. Docking into a homology model of the human GPR17 and molecular dynamic simulation studies rationalized the observed SARs."],["dc.identifier.doi","10.1021/acs.jmedchem.7b01768"],["dc.identifier.pmid","30048589"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/68025"],["dc.language.iso","en"],["dc.relation.eissn","1520-4804"],["dc.relation.issn","0022-2623"],["dc.title","3-(2-Carboxyethyl)indole-2-carboxylic Acid Derivatives: Structural Requirements and Properties of Potent Agonists of the Orphan G Protein-Coupled Receptor GPR17"],["dc.type","journal_article"],["dc.type.internalPublication","no"],["dc.type.subtype","original_ja"],["dspace.entity.type","Publication"]]