Institut für Klinische Pharmakologie

[["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","5462-5480"],["dc.bibliographiccitation.issue","21"],["dc.bibliographiccitation.journal","Bioorganic & Medicinal Chemistry"],["dc.bibliographiccitation.lastpage","5480"],["dc.bibliographiccitation.volume","24"],["dc.contributor.author","Brunschweiger, Andreas"],["dc.contributor.author","Koch, Pierre"],["dc.contributor.author","Schlenk, Miriam"],["dc.contributor.author","Rafehi, Muhammad"],["dc.contributor.author","Radjainia, Hamid"],["dc.contributor.author","Küppers, Petra"],["dc.contributor.author","Hinz, Sonja"],["dc.contributor.author","Pineda, Felipe"],["dc.contributor.author","Wiese, Michael"],["dc.contributor.author","Hockemeyer, Jörg"],["dc.contributor.author","Heer, Jag"],["dc.contributor.author","Denonne, Frédéric"],["dc.contributor.author","Müller, Christa E"],["dc.date.accessioned","2020-09-17T11:31:08Z"],["dc.date.available","2020-09-17T11:31:08Z"],["dc.date.issued","2016"],["dc.description.abstract","Multitarget approaches, i.e., addressing two or more targets simultaneously with a therapeutic agent, are hypothesized to offer additive therapeutic benefit for the treatment of neurodegenerative diseases. Validated targets for the treatment of Parkinson's disease are, among others, the A2A adenosine receptor (AR) and the enzyme monoamine oxidase B (MAO-B). Additional blockade of brain A1 ARs may also be beneficial. We recently described 8-benzyl-substituted tetrahydropyrazino[2,1-f]purinediones as a new lead structure for the development of such multi-target drugs. We have now designed a new series of tetrahydropyrazino[2,1-f]purinediones to extensively explore their structure-activity-relationships. Several compounds blocked human and rat A1 and A2AARs at similar concentrations representing dual A1/A2A antagonists with high selectivity versus the other AR subtypes. Among the best dual A1/A2AAR antagonists were 8-(3-(4-chlorophenyl)propyl)-1,3-dimethyl-6,7,8,9-tetrahydropyrazino[2,1-f]purine-2,4(1H,3H)-dione (41, Ki human A1: 65.5nM, A2A: 230nM; Ki rat A1: 352nM, A2A: 316nM) and 1,3-dimethyl-8-((2-(thiophen-2-yl)thiazol-4-yl)methyl)-6,7,8,9-tetrahydropyrazino[2,1-f]purine-2,4(1H,3H)-dione (57, Ki human A1: 642nM, A2A: 203nM; Ki rat A1: 166nM, A2A: 121nM). Compound 57 was found to be well water-soluble (0.7mg/mL) at a physiological pH value of 7.4. One of the new compounds showed triple-target inhibition: (R)-1,3-dimethyl-8-(2,1,3,4-tetrahydronaphthalen-1-yl)-6,7,8,9-tetrahydropyrazino[2,1-f]purine-2,4(1H,3H)-dione (49) was about equipotent at A1 and A2AARs and at MAO-B (Ki human A1: 393nM, human A2A: 595nM, IC50 human MAO-B: 210nM) thus allowing future in vivo explorations of the intended multi-target approach."],["dc.identifier.doi","10.1016/j.bmc.2016.09.003"],["dc.identifier.pmid","27658798"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/67701"],["dc.language.iso","en"],["dc.relation.eissn","1464-3391"],["dc.relation.issn","0968-0896"],["dc.title","8-Substituted 1,3-dimethyltetrahydropyrazino[2,1-f]purinediones: Water-soluble adenosine receptor antagonists and monoamine oxidase B 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","1507"],["dc.bibliographiccitation.issue","10"],["dc.bibliographiccitation.journal","Biomolecules"],["dc.bibliographiccitation.volume","12"],["dc.contributor.author","Gebauer, Lukas"],["dc.contributor.author","Rafehi, Muhammad"],["dc.contributor.author","Brockmöller, Jürgen"],["dc.contributor.editor","Krause, Frank"],["dc.date.accessioned","2022-12-01T08:31:36Z"],["dc.date.available","2022-12-01T08:31:36Z"],["dc.date.issued","2022"],["dc.date.updated","2022-11-11T13:12:24Z"],["dc.description.abstract","Stereoselectivity is well known and very pronounced in drug metabolism and receptor binding. However, much less is known about stereoselectivity in drug membrane transport. Here, we characterized the stereoselective cell uptake of chiral phenylethylamine derivatives by human monoamine transporters (NET, DAT, and SERT) and organic cation transporters (OCT1, OCT2, and OCT3). Stereoselectivity differed extensively between closely related transporters. High-affinity monoamine transporters (MATs) showed up to 2.4-fold stereoselective uptake of norepinephrine and epinephrine as well as of numerous analogs. While NET and DAT preferentially transported (S)-norepinephrine, SERT preferred the (R)-enantiomer. In contrast, NET and DAT showed higher transport for (R)-epinephrine and SERT for (S)-epinephrine. Generally, MAT stereoselectivity was lower than expected from their high affinity to several catecholamines and from the high stereoselectivity of some inhibitors used as antidepressants. Additionally, the OCTs differed strongly in their stereoselectivity. While OCT1 showed almost no stereoselective uptake, OCT2 was characterized by a roughly 2-fold preference for most (R)-enantiomers of the phenylethylamines. In contrast, OCT3 transported norphenylephrine and phenylephrine with 3.9-fold and 3.3-fold preference for their (R)-enantiomers, respectively, while the para-hydroxylated octopamine and synephrine showed no stereoselective OCT3 transport. Altogether, our data demonstrate that stereoselectivity is highly transporter-to-substrate specific and highly diverse even between homologous transporters."],["dc.description.sponsorship","Deutsche Forschungsgemeinschaft (DFG, German Research Foundation)"],["dc.description.sponsorship","research program of the University Medical Center, University of Göttingen"],["dc.description.sponsorship","Open Access Publication Funds of the Göttingen University"],["dc.identifier.doi","10.3390/biom12101507"],["dc.identifier.pii","biom12101507"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/118216"],["dc.language.iso","en"],["dc.notes.intern","DOI-Import GROB-621"],["dc.publisher","MDPI"],["dc.relation.eissn","2218-273X"],["dc.rights","CC BY 4.0"],["dc.title","Stereoselectivity in the Membrane Transport of Phenylethylamine Derivatives by Human Monoamine Transporters and Organic Cation Transporters 1, 2, and 3"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.version","unpublished"],["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.artnumber","S0006295221004974"],["dc.bibliographiccitation.firstpage","114871"],["dc.bibliographiccitation.journal","Biochemical Pharmacology"],["dc.bibliographiccitation.volume","197"],["dc.contributor.author","Gebauer, Lukas"],["dc.contributor.author","Arul Murugan, N."],["dc.contributor.author","Jensen, Ole"],["dc.contributor.author","Brockmöller, Jürgen"],["dc.contributor.author","Rafehi, Muhammad"],["dc.date.accessioned","2022-01-11T14:07:49Z"],["dc.date.available","2022-01-11T14:07:49Z"],["dc.date.issued","2022"],["dc.identifier.doi","10.1016/j.bcp.2021.114871"],["dc.identifier.pii","S0006295221004974"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/97873"],["dc.language.iso","en"],["dc.notes.intern","DOI-Import GROB-507"],["dc.relation.issn","0006-2952"],["dc.title","Molecular basis for stereoselective transport of fenoterol by the organic cation transporters 1 and 2"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.firstpage","13593"],["dc.bibliographiccitation.issue","17"],["dc.bibliographiccitation.journal","Oncotarget"],["dc.bibliographiccitation.lastpage","13611"],["dc.bibliographiccitation.volume","9"],["dc.contributor.author","Hinz, Sonja"],["dc.contributor.author","Navarro, Gemma"],["dc.contributor.author","Borroto-Escuela, Dasiel"],["dc.contributor.author","Seibt, Benjamin F"],["dc.contributor.author","Ammon, York-Christoph"],["dc.contributor.author","de Filippo, Elisabetta"],["dc.contributor.author","Danish, Azeem"],["dc.contributor.author","Lacher, Svenja K"],["dc.contributor.author","Červinková, Barbora"],["dc.contributor.author","Rafehi, Muhammad"],["dc.contributor.author","Fuxe, Kjell"],["dc.contributor.author","Schiedel, Anke C"],["dc.contributor.author","Franco, Rafael"],["dc.contributor.author","Müller, Christa E"],["dc.date.accessioned","2020-10-22T08:52:21Z"],["dc.date.available","2020-10-22T08:52:21Z"],["dc.date.issued","2018-03-02"],["dc.description.abstract","The adenosine receptor (AR) subtypes A2A and A2B are rhodopsin-like Gs protein-coupled receptors whose expression is highly regulated under pathological, e.g. hypoxic, ischemic and inflammatory conditions. Both receptors play important roles in inflammatory and neurodegenerative diseases, are blocked by caffeine, and have now become major drug targets in immuno-oncology. By Förster resonance energy transfer (FRET), bioluminescence resonance energy transfer (BRET), bimolecular fluorescence complementation (BiFC) and proximity ligation assays (PLA) we demonstrated A2A-A2BAR heteromeric complex formation. Moreover we observed a dramatically altered pharmacology of the A2AAR when co-expressed with the A2BAR (A2B ≥ A2A) in recombinant as well as in native cells. In the presence of A2BARs, A2A-selective ligands lost high affinity binding to A2AARs and displayed strongly reduced potency in cAMP accumulation and dynamic mass redistribution (DMR) assays. These results have major implications for the use of A2AAR ligands as drugs as they will fail to modulate the receptor in an A2A-A2B heteromer context. Accordingly, A2A-A2BAR heteromers represent novel pharmacological targets."],["dc.identifier.doi","10.18632/oncotarget.24423"],["dc.identifier.pmid","29568380"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/68023"],["dc.language.iso","en"],["dc.relation.eissn","1949-2553"],["dc.title","Adenosine A2A receptor ligand recognition and signaling is blocked by A2B receptors"],["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"]]

[["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"]]