Structural Determinants for the Mode of Action of Imidazopyridine DS2 at δ-Containing γ-Aminobutyric Acid Type A Receptors
- Publication type:
- Journal article
- Metadata:
-
- Autoren
- Frederik Rostrup
- Christina B Falk-Petersen
- Kasper Harpsoe
- Stine Buchleithner
- Irene Conforti
- Sascha Jung
- David E Gloriam
- Tanja Schirmeister
- Petrine Wellendorph
- Bente Frolund
- Autoren-URL
- https://www.webofscience.com/api/gateway?GWVersion=2&SrcApp=fis-test-1&SrcAuth=WosAPI&KeyUT=WOS:000644437100024&DestLinkType=FullRecord&DestApp=WOS_CPL
- DOI
- 10.1021/acs.jmedchem.0c02163
- eISSN
- 1520-4804
- Externe Identifier
- Clarivate Analytics Document Solution ID: RT4NH
- PubMed Identifier: 33847501
- ISSN
- 0022-2623
- Ausgabe der Veröffentlichung
- 8
- Zeitschrift
- JOURNAL OF MEDICINAL CHEMISTRY
- Paginierung
- 4730 - 4743
- Datum der Veröffentlichung
- 2021
- Status
- Published
- Titel
- Structural Determinants for the Mode of Action of Imidazopyridine DS2 at δ-Containing γ-Aminobutyric Acid Type A Receptors
- Sub types
- Article
- Ausgabe der Zeitschrift
- 64
Data source: Web of Science (Lite)
- Other metadata sources:
-
- Autoren
- Frederik Rostrup
- Christina B Falk-Petersen
- Kasper Harpsøe
- Stine Buchleithner
- Irene Conforti
- Sascha Jung
- David E Gloriam
- Tanja Schirmeister
- Petrine Wellendorph
- Bente Frølund
- DOI
- 10.1021/acs.jmedchem.0c02163
- eISSN
- 1520-4804
- ISSN
- 0022-2623
- Ausgabe der Veröffentlichung
- 8
- Zeitschrift
- Journal of Medicinal Chemistry
- Sprache
- en
- Online publication date
- 2021
- Paginierung
- 4730 - 4743
- Datum der Veröffentlichung
- 2021
- Status
- Published
- Herausgeber
- American Chemical Society (ACS)
- Herausgeber URL
- http://dx.doi.org/10.1021/acs.jmedchem.0c02163
- Datum der Datenerfassung
- 2023
- Titel
- Structural Determinants for the Mode of Action of Imidazopyridine DS2 at δ-Containing γ-Aminobutyric Acid Type A Receptors
- Ausgabe der Zeitschrift
- 64
Data source: Crossref
- Abstract
- Despite the therapeutic relevance of δ-containing γ-aminobutyric acid type A receptors (GABA<sub>A</sub>Rs) and the need for δ-selective compounds, the structural determinants for the mode and molecular site of action of δ-selective positive allosteric modulator imidazo[1,2-a]pyridine DS2 remain elusive. To guide the quest for insight, we synthesized a series of DS2 analogues guided by a structural receptor model. Using a fluorescence-based fluorometric imaging plate reader membrane potential assay, we found that the δ-selectivity and the pharmacological profile are severely affected by substituents in the 5-position of the imidazopyridine core scaffold. Interestingly, the 5-methyl, 5-bromo, and 5-chloro DS2 analogues, <b>30</b>, <b>35,</b> and <b>36,</b> were shown to be superior to DS2 at α4β1δ as mid-high nanomolar potency δ-selective allosteric modulators, displaying 6-16 times higher potency than DS2. Of these, <b>30</b> also displayed at least 60-fold selectivity for α4β1δ over α4β1γ2 receptor subtypes representing a potential tool for the selective characterization of δ-containing GABA<sub>A</sub>Rs in general.
- Addresses
- Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, Copenhagen DK-2100, Denmark.
- Autoren
- Frederik Rostrup
- Christina B Falk-Petersen
- Kasper Harpso E
- Stine Buchleithner
- Irene Conforti
- Sascha Jung
- David E Gloriam
- Tanja Schirmeister
- Petrine Wellendorph
- Bente Fro Lund
- DOI
- 10.1021/acs.jmedchem.0c02163
- eISSN
- 1520-4804
- Externe Identifier
- PubMed Identifier: 33847501
- Funding acknowledgements
- Lundbeckfonden: R230-2016-2562
- Drug Research Academy, Københavns Universitet:
- Lundbeck Foundation: R230-2016-2562
- Open access
- false
- ISSN
- 0022-2623
- Ausgabe der Veröffentlichung
- 8
- Zeitschrift
- Journal of medicinal chemistry
- Schlüsselwörter
- Humans
- Pyridines
- Receptors, GABA-A
- Protein Subunits
- Ligands
- Allosteric Regulation
- Binding Sites
- Structure-Activity Relationship
- Drug Design
- HEK293 Cells
- Molecular Docking Simulation
- Sprache
- eng
- Medium
- Print-Electronic
- Online publication date
- 2021
- Paginierung
- 4730 - 4743
- Datum der Veröffentlichung
- 2021
- Status
- Published
- Datum der Datenerfassung
- 2021
- Titel
- Structural Determinants for the Mode of Action of Imidazopyridine DS2 at δ-Containing γ-Aminobutyric Acid Type A Receptors.
- Sub types
- Research Support, Non-U.S. Gov't
- Journal Article
- Ausgabe der Zeitschrift
- 64
Data source: Europe PubMed Central
- Abstract
- Despite the therapeutic relevance of δ-containing γ-aminobutyric acid type A receptors (GABAARs) and the need for δ-selective compounds, the structural determinants for the mode and molecular site of action of δ-selective positive allosteric modulator imidazo[1,2-a]pyridine DS2 remain elusive. To guide the quest for insight, we synthesized a series of DS2 analogues guided by a structural receptor model. Using a fluorescence-based fluorometric imaging plate reader membrane potential assay, we found that the δ-selectivity and the pharmacological profile are severely affected by substituents in the 5-position of the imidazopyridine core scaffold. Interestingly, the 5-methyl, 5-bromo, and 5-chloro DS2 analogues, 30, 35, and 36, were shown to be superior to DS2 at α4β1δ as mid-high nanomolar potency δ-selective allosteric modulators, displaying 6-16 times higher potency than DS2. Of these, 30 also displayed at least 60-fold selectivity for α4β1δ over α4β1γ2 receptor subtypes representing a potential tool for the selective characterization of δ-containing GABAARs in general.
- Autoren
- Frederik Rostrup
- Christina B Falk-Petersen
- Kasper Harpso E
- Stine Buchleithner
- Irene Conforti
- Sascha Jung
- David E Gloriam
- Tanja Schirmeister
- Petrine Wellendorph
- Bente Fro Lund
- Autoren-URL
- https://www.ncbi.nlm.nih.gov/pubmed/33847501
- DOI
- 10.1021/acs.jmedchem.0c02163
- eISSN
- 1520-4804
- Ausgabe der Veröffentlichung
- 8
- Zeitschrift
- J Med Chem
- Schlüsselwörter
- Allosteric Regulation
- Binding Sites
- Drug Design
- HEK293 Cells
- Humans
- Ligands
- Molecular Docking Simulation
- Protein Subunits
- Pyridines
- Receptors, GABA-A
- Structure-Activity Relationship
- Sprache
- eng
- Country
- United States
- Paginierung
- 4730 - 4743
- Datum der Veröffentlichung
- 2021
- Status
- Published
- Datum, an dem der Datensatz öffentlich gemacht wurde
- 2021
- Titel
- Structural Determinants for the Mode of Action of Imidazopyridine DS2 at δ-Containing γ-Aminobutyric Acid Type A Receptors.
- Sub types
- Journal Article
- Research Support, Non-U.S. Gov't
- Ausgabe der Zeitschrift
- 64
Data source: PubMed
- Autoren
- Frederik Rostrup
- Christina B Falk-Petersen
- Kasper Harpso̷e
- Stine Buchleithner
- Irene Conforti
- Sascha Jung
- David E Gloriam
- Tanja Schirmeister
- Petrine Wellendorph
- Bente Fro̷lund
- Zeitschrift
- Journal of Medicinal Chemistry
- Datum der Veröffentlichung
- 2021
- Herausgeber
- ACS Publications
- Datum der Datenerfassung
- 2021
- Titel
- Structural Determinants for the Mode of Action of Imidazopyridine DS2 at δ-Containing γ-Aminobutyric Acid Type A Receptors
- Sub types
- article
Data source: Manual
- Beziehungen:
- Property of