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Discovery of G Protein-Biased Dopaminergics with a Pyrazolo[1,5‑a]pyridine Substructure
journal contribution
posted on 2017-03-01, 00:00 authored by 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 Gmeiner1,4-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.
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lipophilic moietypropyl -2-aminotetraline unithigh-affinity dopamine receptorG protein-biased dopaminergic ligandsBRET biosensorsβ- arrestin recruitmentagonistnovel therapeuticsincrease binding affinityG proteinscomplementation-based assaysrepresentative 2- methoxyphenylpiperazine 16 caminergic G protein-coupled receptorsdopamine D 2 receptorsappendage5- hydroxyantipsychotic activitypyridinearylpiperazine corepyrazolodesign G protein-biasedbinding studiesG Protein-Biased Dopaminergics
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