Seemann, Wiebke K., Wenzel, Daniela ORCID: 0000-0003-1100-6363, Schrage, Ramona, Etscheid, Justine, Boedefeld, Theresa, Bartol, Anna, Warnken, Mareille, Sasse, Philipp ORCID: 0000-0002-8502-9472, Kloeckner, Jessica, Holzgrabe, Ulrike, DeAmici, Marco, Schlicker, Eberhard, Racke, Kurt, Kostenis, Evi, Meyer, Rainer, Fleischmann, Bernd K. and Mohr, Klaus (2017). Engineered Context-Sensitive Agonism: Tissue-Selective Drug Signaling through a G Protein-Coupled Receptor. J. Pharmacol. Exp. Ther., 360 (2). S. 289 - 300. BETHESDA: AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS. ISSN 1521-0103

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Abstract

Drug discovery strives for selective ligands to achieve targeted modulation of tissue function. Here we introduce engineered context-sensitive agonism as a postreceptor mechanism for tissue-selective drug action through a G protein-coupled receptor. Acetylcholine M2-receptor activation is known to mediate, among other actions, potentially dangerous slowing of the heart rate. This unwanted side effect is one of the main reasons that limit clinical application of muscarinic agonists. Herein we show that dualsteric (orthosteric/allosteric) agonists induce less cardiac depression ex vivo and in vivo than conventional full agonists. Exploration of the underlying mechanism in living cells employing cellular dynamic mass redistribution identified context-sensitive agonism of these dualsteric agonists. They translate elevation of intracellular cAMP into a switch from full to partial agonism. Designed context-sensitive agonism opens an avenue toward postreceptor pharmacologic selectivity, which even works in target tissues operated by the same subtype of pharmacologic receptor.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Seemann, Wiebke K.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wenzel, DanielaUNSPECIFIEDorcid.org/0000-0003-1100-6363UNSPECIFIED
Schrage, RamonaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Etscheid, JustineUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Boedefeld, TheresaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bartol, AnnaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Warnken, MareilleUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Sasse, PhilippUNSPECIFIEDorcid.org/0000-0002-8502-9472UNSPECIFIED
Kloeckner, JessicaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Holzgrabe, UlrikeUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
DeAmici, MarcoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schlicker, EberhardUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Racke, KurtUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kostenis, EviUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Meyer, RainerUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Fleischmann, Bernd K.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Mohr, KlausUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-241298
DOI: 10.1124/jpet.116.237149
Journal or Publication Title: J. Pharmacol. Exp. Ther.
Volume: 360
Number: 2
Page Range: S. 289 - 300
Date: 2017
Publisher: AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS
Place of Publication: BETHESDA
ISSN: 1521-0103
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
MUSCARINIC ACETYLCHOLINE-RECEPTORS; HEART-RATE; KNOCKOUT MICE; PHARMACOLOGICAL AGONISM; ANALGESIC ACTIVITY; ADENYLYL-CYCLASE; INHIBITION; EFFICACY; CELLS; MOUSEMultiple languages
Pharmacology & PharmacyMultiple languages
Refereed: Yes
URI: http://kups.ub.uni-koeln.de/id/eprint/24129

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