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","129501"],["dc.bibliographiccitation.issue","3"],["dc.bibliographiccitation.journal","Biochimica et Biophysica Acta. General Subjects"],["dc.bibliographiccitation.volume","1864"],["dc.contributor.author","Attah, Isaac Y"],["dc.contributor.author","Neumann, Alexander"],["dc.contributor.author","Al-Hroub, Haneen"],["dc.contributor.author","Rafehi, Muhammad"],["dc.contributor.author","Baqi, Younis"],["dc.contributor.author","Namasivayam, Vigneshwaran"],["dc.contributor.author","Müller, Christa E"],["dc.date.accessioned","2020-10-22T08:56:11Z"],["dc.date.available","2020-10-22T08:56:11Z"],["dc.date.issued","2020"],["dc.description.abstract","The nucleotide receptors P2Y2 and P2Y4 are the most closely related G protein-coupled receptors (GPCRs) of the P2Y receptor (P2YR) family. Both subtypes couple to Gq proteins and are activated by the pyrimidine nucleotide UTP, but only P2Y2R is also activated by the purine nucleotide ATP. Agonists and antagonists of both receptor subtypes have potential as drugs e.g. for neurodegenerative and inflammatory diseases. So far, potent and selective, \"drug-like\" ligands for both receptors are scarce, but would be required for target validation and as lead structures for drug development. Structural information on the receptors is lacking since no X-ray structures or cryo-electron microscopy images are available. Thus, we performed receptor homology modeling and docking studies combined with mutagenesis experiments on both receptors to address the question how ligand binding selectivity for these closely related P2YR subtypes can be achieved. The orthosteric binding site of P2Y2R appeared to be more spacious than that of P2Y4R. Mutation of Y197 to alanine in P2Y4R resulted in a gain of ATP sensitivity. Anthraquinone-derived antagonists are likely to bind to the orthosteric or an allosteric site depending on their substitution pattern and the nature of the orthosteric binding site of the respective P2YR subtype. These insights into the architecture of P2Y2- and P2Y4Rs and their interactions with structurally diverse agonists and antagonist provide a solid basis for the future design of potent and selective ligands."],["dc.identifier.doi","10.1016/j.bbagen.2019.129501"],["dc.identifier.pmid","31812541"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/68029"],["dc.language.iso","en"],["dc.relation.eissn","1872-8006"],["dc.relation.issn","0304-4165"],["dc.relation.orgunit","Institut für Klinische Pharmakologie"],["dc.title","Ligand binding and activation of UTP-activated G protein-coupled P2Y2 and P2Y4 receptors elucidated by mutagenesis, pharmacological and computational studies"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["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"]]

[["dc.bibliographiccitation.firstpage","105880"],["dc.bibliographiccitation.journal","Pharmacological Research"],["dc.bibliographiccitation.volume","173"],["dc.contributor.author","Voss, Jan H."],["dc.contributor.author","Nagel, Jessica"],["dc.contributor.author","Rafehi, Muhammad"],["dc.contributor.author","Guixà-González, Ramon"],["dc.contributor.author","Malfacini, Davide"],["dc.contributor.author","Patt, Julian"],["dc.contributor.author","Kehraus, Stefan"],["dc.contributor.author","Inoue, Asuka"],["dc.contributor.author","König, Gabriele M."],["dc.contributor.author","Kostenis, Evi"],["dc.contributor.author","Deupi, Xavier"],["dc.contributor.author","Namasivayam, Vigneshwaran"],["dc.contributor.author","Müller, Christa E."],["dc.date.accessioned","2022-02-15T12:26:04Z"],["dc.date.available","2022-02-15T12:26:04Z"],["dc.date.issued","2021"],["dc.description.abstract","G proteins represent intracellular switches that transduce signals relayed from G protein-coupled receptors. The structurally related macrocyclic depsipeptides FR900359 (FR) and YM-254890 (YM) are potent, selective inhibitors of the Gαq protein family. We recently discovered that radiolabeled FR and YM display strongly divergent residence times, which translates into significantly longer antiasthmatic effects of FR. The present study is aimed at investigating the molecular basis for this observed disparity. Based on docking studies, we mutated amino acid residues of the Gαq protein predicted to interact with FR or YM, and recombinantly expressed the mutated Gαq proteins in cells in which the native Gαq proteins had been knocked out by CRISPR-Cas9. Both radioligands showed similar association kinetics, and their binding followed a conformational selection mechanism, which was rationalized by molecular dynamics simulation studies. Several mutations of amino acid residues near the putative binding site of the \"lipophilic anchors\" of FR, especially those predicted to interact with the isopropyl group present in FR but not in YM, led to dramatically accelerated dissociation kinetics. Our data indicate that the long residence time of FR depends on lipophilic interactions within its binding site. The observed structure-kinetic relationships point to a complex binding mechanism of FR, which likely involves snap-lock- or dowel-like conformational changes of either ligand or protein, or both. These experimental data will be useful for the design of compounds with a desired residence time, a parameter that has now been recognized to be of utmost importance in drug development."],["dc.identifier.doi","10.1016/j.phrs.2021.105880"],["dc.identifier.pmid","34506902"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/99901"],["dc.language.iso","en"],["dc.relation.eissn","1096-1186"],["dc.relation.issn","1043-6618"],["dc.title","Unraveling binding mechanism and kinetics of macrocyclic Gαq protein inhibitors"],["dc.type","journal_article"],["dc.type.internalPublication","no"],["dc.type.subtype","original_ja"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.firstpage","8425"],["dc.bibliographiccitation.issue","20"],["dc.bibliographiccitation.journal","Journal of Medicinal Chemistry"],["dc.bibliographiccitation.lastpage","8440"],["dc.bibliographiccitation.volume","60"],["dc.contributor.author","Rafehi, Muhammad"],["dc.contributor.author","Neumann, Alexander"],["dc.contributor.author","Baqi, Younis"],["dc.contributor.author","Malik, Enas M"],["dc.contributor.author","Wiese, Michael"],["dc.contributor.author","Namasivayam, Vigneshwaran"],["dc.contributor.author","Müller, Christa E"],["dc.date.accessioned","2020-10-22T08:52:12Z"],["dc.date.available","2020-10-22T08:52:12Z"],["dc.date.issued","2017"],["dc.description.abstract","A homology model of the nucleotide-activated P2Y2R was created based on the X-ray structures of the P2Y1 receptor. Docking studies were performed, and receptor mutants were created to probe the identified binding interactions. Mutation of residues predicted to interact with the ribose (Arg110) and the phosphates of the nucleotide agonists (Arg265, Arg292) or that contribute indirectly to binding (Tyr288) abolished activity. The Y114F, R194A, and F261A mutations led to inactivity of diadenosine tetraphosphate and to a reduced response of UTP. Significant reduction in agonist potency was observed for all other receptor mutants (Phe111, His184, Ser193, Phe261, Tyr268, Tyr269) predicted to be involved in agonist recognition. An ionic lock between Asp185 and Arg292 that is probably involved in receptor activation interacts with the phosphate groups. The antagonist AR-C118925 and anthraquinones likely bind to the orthosteric site. The updated homology models will be useful for virtual screening and drug design."],["dc.identifier.doi","10.1021/acs.jmedchem.7b00854"],["dc.identifier.pmid","28938069"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/68022"],["dc.language.iso","en"],["dc.relation.eissn","1520-4804"],["dc.relation.issn","0022-2623"],["dc.title","Molecular Recognition of Agonists and Antagonists by the Nucleotide-Activated G Protein-Coupled P2Y2 Receptor"],["dc.type","journal_article"],["dc.type.internalPublication","no"],["dc.type.subtype","original_ja"],["dspace.entity.type","Publication"]]