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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 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.

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