Discovery of G Protein-Biased Dopaminergics with a Pyrazolo[1,5-a]pyridine Substructure
- Publikationstyp:
- Zeitschriftenaufsatz
- Metadaten:
-
- Autoren
- Dorothee Moeller
- Ashutosh Banerjee
- Taygun C Uzuneser
- Marika Skultety
- Tobias Huth
- Bianca Plouffe
- Harald Huebner
- Christian Alzheimer
- Kristina Friedland
- Christian P Mueller
- Michel Bouvier
- Peter Gmeiner
- Autoren-URL
- https://www.webofscience.com/api/gateway?GWVersion=2&SrcApp=fis-test-1&SrcAuth=WosAPI&KeyUT=WOS:000399436100020&DestLinkType=FullRecord&DestApp=WOS_CPL
- DOI
- 10.1021/acs.jmedchem.6b01857
- eISSN
- 1520-4804
- Externe Identifier
- Clarivate Analytics Document Solution ID: ES3NK
- PubMed Identifier: 28248104
- ISSN
- 0022-2623
- Ausgabe der Veröffentlichung
- 7
- Zeitschrift
- JOURNAL OF MEDICINAL CHEMISTRY
- Paginierung
- 2908 - 2929
- Datum der Veröffentlichung
- 2017
- Status
- Published
- Titel
- Discovery of G Protein-Biased Dopaminergics with a Pyrazolo[1,5-<i>a</i>]pyridine Substructure
- Sub types
- Article
- Ausgabe der Zeitschrift
- 60
Datenquelle: Web of Science (Lite)
- Andere Metadatenquellen:
-
- Autoren
- Dorothee Möller
- Ashutosh Banerjee
- Taygun C Uzuneser
- Marika Skultety
- Tobias Huth
- Bianca Plouffe
- Harald Hübner
- Christian Alzheimer
- Kristina Friedland
- Christian P Müller
- Michel Bouvier
- Peter Gmeiner
- DOI
- 10.1021/acs.jmedchem.6b01857
- eISSN
- 1520-4804
- ISSN
- 0022-2623
- Ausgabe der Veröffentlichung
- 7
- Zeitschrift
- Journal of Medicinal Chemistry
- Sprache
- en
- Online publication date
- 2017
- Paginierung
- 2908 - 2929
- Datum der Veröffentlichung
- 2017
- Status
- Published
- Herausgeber
- American Chemical Society (ACS)
- Herausgeber URL
- http://dx.doi.org/10.1021/acs.jmedchem.6b01857
- Datum der Datenerfassung
- 2023
- Titel
- Discovery of G Protein-Biased Dopaminergics with a Pyrazolo[1,5-<i>a</i>]pyridine Substructure
- Ausgabe der Zeitschrift
- 60
Datenquelle: Crossref
- Abstract
- 1,4-Disubstituted aromatic piperazines are privileged structural motifs recognized by aminergic G protein-coupled receptors. Connection of a lipophilic moiety to the arylpiperazine core by an appropriate linker represents a promising concept to increase binding affinity and to fine-tune functional properties. In particular, incorporation of a pyrazolo[1,5-a]pyridine heterocyclic appendage led to a series of high-affinity dopamine receptor partial agonists. Comprehensive pharmacological characterization involving BRET biosensors, binding studies, electrophysiology, and complementation-based assays revealed compounds favoring activation of G proteins (preferably G<sub>o</sub>) over β-arrestin recruitment at dopamine D<sub>2</sub> receptors. The feasibility to design G protein-biased partial agonists as putative novel therapeutics was demonstrated for the representative 2-methoxyphenylpiperazine 16c, which unequivocally displayed antipsychotic activity in vivo. Moreover, combination of the pyrazolo[1,5-a]pyridine appendage with a 5-hydroxy-N-propyl-2-aminotetraline unit led to balanced or G protein-biased dopaminergic ligands depending on the stereochemistry of the headgroup, illustrating the complex structure-functional selectivity relationships at dopamine D<sub>2</sub> receptors.
- Addresses
- Department of Chemistry and Pharmacy, Medicinal Chemistry, Friedrich-Alexander University Erlangen-Nürnberg , Schuhstraße 19, 91052 Erlangen, Germany.
- Autoren
- Dorothee Möller
- Ashutosh Banerjee
- Taygun C Uzuneser
- Marika Skultety
- Tobias Huth
- Bianca Plouffe
- Harald Hübner
- Christian Alzheimer
- Kristina Friedland
- Christian P Müller
- Michel Bouvier
- Peter Gmeiner
- DOI
- 10.1021/acs.jmedchem.6b01857
- eISSN
- 1520-4804
- Externe Identifier
- PubMed Identifier: 28248104
- Funding acknowledgements
- Canadian Institutes of Health Research: 11215
- Deutsche Forschungsgemeinschaft: GRK1910
- Deutsche Forschungsgemeinschaft: MU 2789/7-1
- Open access
- false
- ISSN
- 0022-2623
- Ausgabe der Veröffentlichung
- 7
- Zeitschrift
- Journal of medicinal chemistry
- Schlüsselwörter
- Animals
- Humans
- Rats
- Rats, Sprague-Dawley
- Pyrazoles
- Pyridines
- GTP-Binding Proteins
- Receptors, Dopamine D2
- Dopamine Agonists
- Antipsychotic Agents
- Schizophrenia
- Male
- Drug Discovery
- beta-Arrestins
- Sprache
- eng
- Medium
- Print-Electronic
- Online publication date
- 2017
- Paginierung
- 2908 - 2929
- Datum der Veröffentlichung
- 2017
- Status
- Published
- Datum der Datenerfassung
- 2017
- Titel
- Discovery of G Protein-Biased Dopaminergics with a Pyrazolo[1,5-a]pyridine Substructure.
- Sub types
- Research Support, Non-U.S. Gov't
- Journal Article
- Ausgabe der Zeitschrift
- 60
Datenquelle: Europe PubMed Central
- Abstract
- 1,4-Disubstituted aromatic piperazines are privileged structural motifs recognized by aminergic G protein-coupled receptors. Connection of a lipophilic moiety to the arylpiperazine core by an appropriate linker represents a promising concept to increase binding affinity and to fine-tune functional properties. In particular, incorporation of a pyrazolo[1,5-a]pyridine heterocyclic appendage led to a series of high-affinity dopamine receptor partial agonists. Comprehensive pharmacological characterization involving BRET biosensors, binding studies, electrophysiology, and complementation-based assays revealed compounds favoring activation of G proteins (preferably Go) over β-arrestin recruitment at dopamine D2 receptors. The feasibility to design G protein-biased partial agonists as putative novel therapeutics was demonstrated for the representative 2-methoxyphenylpiperazine 16c, which unequivocally displayed antipsychotic activity in vivo. Moreover, combination of the pyrazolo[1,5-a]pyridine appendage with a 5-hydroxy-N-propyl-2-aminotetraline unit led to balanced or G protein-biased dopaminergic ligands depending on the stereochemistry of the headgroup, illustrating the complex structure-functional selectivity relationships at dopamine D2 receptors.
- Autoren
- Dorothee Möller
- Ashutosh Banerjee
- Taygun C Uzuneser
- Marika Skultety
- Tobias Huth
- Bianca Plouffe
- Harald Hübner
- Christian Alzheimer
- Kristina Friedland
- Christian P Müller
- Michel Bouvier
- Peter Gmeiner
- Autoren-URL
- https://www.ncbi.nlm.nih.gov/pubmed/28248104
- DOI
- 10.1021/acs.jmedchem.6b01857
- eISSN
- 1520-4804
- Ausgabe der Veröffentlichung
- 7
- Zeitschrift
- J Med Chem
- Schlüsselwörter
- Animals
- Antipsychotic Agents
- Dopamine Agonists
- Drug Discovery
- GTP-Binding Proteins
- Humans
- Male
- Pyrazoles
- Pyridines
- Rats
- Rats, Sprague-Dawley
- Receptors, Dopamine D2
- Schizophrenia
- beta-Arrestins
- Sprache
- eng
- Country
- United States
- Paginierung
- 2908 - 2929
- Datum der Veröffentlichung
- 2017
- Status
- Published
- Datum, an dem der Datensatz öffentlich gemacht wurde
- 2017
- Titel
- Discovery of G Protein-Biased Dopaminergics with a Pyrazolo[1,5-a]pyridine Substructure.
- Sub types
- Journal Article
- Research Support, Non-U.S. Gov't
- Ausgabe der Zeitschrift
- 60
Datenquelle: PubMed
- Beziehungen:
- Eigentum von