Discovery of G Protein-Biased Dopaminergics with a Pyrazolo[1,5‑<i>a</i>]pyridine Substructure
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
10.1021/acs.jmedchem.6b01857.s002
https://acs.figshare.com/articles/dataset/Discovery_of_G_Protein-Biased_Dopaminergics_with_a_Pyrazolo_1_5_i_a_i_pyridine_Substructure/4776541
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-<i>a</i>]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 <b>16c</b>, which unequivocally displayed
antipsychotic activity in vivo. Moreover, combination of the pyrazolo[1,5-<i>a</i>]pyridine appendage with a 5-hydroxy-<i>N</i>-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.
2017-03-01 00:00:00
lipophilic moiety
propyl -2-aminotetraline unit
high-affinity dopamine receptor
G protein-biased dopaminergic ligands
BRET biosensors
β- arrestin recruitment
agonist
novel therapeutics
increase binding affinity
G proteins
complementation-based assays
representative 2- methoxyphenylpiperazine 16 c
aminergic G protein-coupled receptors
dopamine D 2 receptors
appendage
5- hydroxy
antipsychotic activity
pyridine
arylpiperazine core
pyrazolo
design G protein-biased
binding studies
G Protein-Biased Dopaminergics