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.s001 https://acs.figshare.com/articles/journal_contribution/Discovery_of_G_Protein-Biased_Dopaminergics_with_a_Pyrazolo_1_5_i_a_i_pyridine_Substructure/4776544 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