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

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posted on 01.03.2017, 00:00 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 Gmeiner
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 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.