Discovery of G Protein-Biased Dopaminergics with a Pyrazolo[1,5-a]pyridine Substructure

Beitrag in einer Fachzeitschrift

Details zur Publikation

Autorinnen und Autoren: Möller D, Banerjee A, Uzuneser T, Skultety M, Huth T, Plouffe B, Hübner H, Alzheimer C, Friedland K, Müller CP, Bouvier M, Gmeiner P
Zeitschrift: Journal of Medicinal Chemistry
Jahr der Veröffentlichung: 2017
Band: 60
Heftnummer: 7
Seitenbereich: 2908-2929
ISSN: 0022-2623


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(o)) over beta-arrestin recruitment at dopamine D-2 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-propy1-2-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.

FAU-Autorinnen und Autoren / FAU-Herausgeberinnen und Herausgeber

Alzheimer, Christian Prof. Dr.
Lehrstuhl für Physiologie
Banerjee, Ashutosh Dr.
Lehrstuhl für Pharmazeutische Chemie
Friedland, Kristina Prof. Dr.
Professur für Molekulare und Klinische Pharmazie
Gmeiner, Peter Prof. Dr.
Lehrstuhl für Pharmazeutische Chemie
Hübner, Harald Dr.
Lehrstuhl für Pharmazeutische Chemie
Huth, Tobias PD Dr. Dr.
Lehrstuhl für Physiologie
Weikert, Dorothee Dr.
Lehrstuhl für Pharmazeutische Chemie
Müller, Christian P. Prof. Dr.
Professur für Suchtmedizin
Uzuneser, Taygun
Professur für Suchtmedizin

Zusätzliche Organisationseinheit(en)
Emil-Fischer-Zentrum (Emil Fischer Center)

Einrichtungen weiterer Autorinnen und Autoren

Université de Montréal


Möller, D., Banerjee, A., Uzuneser, T., Skultety, M., Huth, T., Plouffe, B.,... Gmeiner, P. (2017). Discovery of G Protein-Biased Dopaminergics with a Pyrazolo[1,5-a]pyridine Substructure. Journal of Medicinal Chemistry, 60(7), 2908-2929.

Möller, Dorothee, et al. "Discovery of G Protein-Biased Dopaminergics with a Pyrazolo[1,5-a]pyridine Substructure." Journal of Medicinal Chemistry 60.7 (2017): 2908-2929.


Zuletzt aktualisiert 2019-25-02 um 07:09