Discovery of G Protein-Biased Dopaminergics with a Pyrazolo[1,5-a]pyridine Substructure
Möller D, Banerjee A, Uzuneser T, Skultety M, Huth T, Plouffe B, Hübner H, Alzheimer C, Friedland K, Müller CP, Bouvier M, Gmeiner P (2017)
Publication Status: Published
Publication Type: Journal article, Original article
Publication year: 2017
Journal
Publisher: AMER CHEMICAL SOC
Book Volume: 60
Pages Range: 2908-2929
Journal Issue: 7
DOI: 10.1021/acs.jmedchem.6b01857
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.
Authors with CRIS profile
Dorothée Weikert
Lehrstuhl für Pharmazeutische Chemie
Ashutosh Banerjee
Lehrstuhl für Pharmazeutische Chemie
Taygun Uzuneser
Professur für Suchtmedizin
Tobias Huth
Lehrstuhl für Physiologie
Harald Hübner
Lehrstuhl für Pharmazeutische Chemie
Christian Alzheimer
Lehrstuhl für Physiologie
Kristina Friedland
Professur für Molekulare und Klinische Pharmazie
Peter Christian Müller
Professur für Suchtmedizin
Peter Gmeiner
Lehrstuhl für Pharmazeutische Chemie
Additional Organisation(s)
Involved external institutions
Canada (CA)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://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.
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