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

Möller D, Banerjee A, Uzuneser T, Skultety M, Huth T, Plouffe B, Hübner H, Alzheimer C, Friedland K, Müller CP, Bouvier M, Gmeiner P (2017)


Publication Status: Published

Publication Type: Journal article, Original article

Publication year: 2017

Journal

Publisher: AMER CHEMICAL SOC

Book Volume: 60

Pages Range: 2908-2929

Journal Issue: 7

DOI: 10.1021/acs.jmedchem.6b01857

Abstract

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 G(o)) over beta-arrestin recruitment at dopamine D-2 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-propy1-2-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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How to cite

APA:

Möller, D., Banerjee, A., Uzuneser, T., Skultety, M., Huth, T., Plouffe, B.,... Gmeiner, P. (2017). Discovery of G Protein-Biased Dopaminergics with a Pyrazolo[1,5-a]pyridine Substructure. Journal of Medicinal Chemistry, 60(7), 2908-2929. https://dx.doi.org/10.1021/acs.jmedchem.6b01857

MLA:

Möller, Dorothee, et al. "Discovery of G Protein-Biased Dopaminergics with a Pyrazolo[1,5-a]pyridine Substructure." Journal of Medicinal Chemistry 60.7 (2017): 2908-2929.

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