Discovery of G Protein-Biased Dopaminergics with a Pyrazolo[1,5‑<i>a</i>]pyridine Substructure

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.