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

Journal article
(Original article)


Publication Details

Author(s): Möller D, Banerjee A, Uzuneser T, Skultety M, Huth T, Plouffe B, Hübner H, Alzheimer C, Friedland K, Müller CP, Bouvier M, Gmeiner P
Journal: Journal of Medicinal Chemistry
Publisher: AMER CHEMICAL SOC
Publication year: 2017
Volume: 60
Journal issue: 7
Pages range: 2908-2929
ISSN: 0022-2623


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(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 Authors / FAU Editors

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


Additional Organisation
Emil-Fischer-Zentrum (Emil Fischer Center)


External institutions
Université de Montréal


How to cite

APA:
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. https://dx.doi.org/10.1021/acs.jmedchem.6b01857

MLA:
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.

BibTeX: 

Last updated on 2019-25-02 at 07:09