title: Discovery of G Protein-Biased Dopaminergics with a Pyrazolo[1,5-a]pyridine Substructure.
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 Go) over β-arrestin recruitment at dopamine D2receptors. 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 D2receptors.
authors.affiliation: Department of Chemistry and Pharmacy, Medicinal Chemistry, Friedrich-Alexander University Erlangen-Nürnberg , Schuhstraße 19, 91052 Erlangen, Germany.
authors.forename: Dorothee
authors.initials: D
authors.lastname: Möller
authors.affiliation: Department of Chemistry and Pharmacy, Medicinal Chemistry, Friedrich-Alexander University Erlangen-Nürnberg , Schuhstraße 19, 91052 Erlangen, Germany.
authors.forename: Ashutosh
authors.initials: A
authors.lastname: Banerjee
authors.affiliation: Department of Psychiatry and Psychotherapy, Friedrich-Alexander University Erlangen-Nürnberg , Schwabachanlage 6, 91054 Erlangen, Germany.
authors.forename: Taygun C
authors.initials: TC
authors.lastname: Uzuneser
authors.affiliation: Department of Chemistry and Pharmacy, Medicinal Chemistry, Friedrich-Alexander University Erlangen-Nürnberg , Schuhstraße 19, 91052 Erlangen, Germany.
authors.forename: Marika
authors.initials: M
authors.lastname: Skultety
authors.affiliation: Institute of Physiology and Pathophysiology, Friedrich-Alexander University Erlangen-Nürnberg , Universitätsstraße 17, 91054 Erlangen, Germany.
authors.forename: Tobias
authors.initials: T
authors.lastname: Huth
authors.affiliation: Institute for Research in Immunology and Cancer (IRIC), Department of Biochemistry and Molecular Medicine, University of Montreal , Québec, Canada H3C 1J4.
authors.forename: Bianca
authors.initials: B
authors.lastname: Plouffe
authors.affiliation: Department of Chemistry and Pharmacy, Medicinal Chemistry, Friedrich-Alexander University Erlangen-Nürnberg , Schuhstraße 19, 91052 Erlangen, Germany.
authors.forename: Harald
authors.initials: H
authors.lastname: Hübner
authors.affiliation: Institute of Physiology and Pathophysiology, Friedrich-Alexander University Erlangen-Nürnberg , Universitätsstraße 17, 91054 Erlangen, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Alzheimer
authors.affiliation: Department of Chemistry and Pharmacy, Molecular and Clinical Pharmacy, Friedrich-Alexander University Erlangen-Nürnberg , Cauerstraße 4, 91058 Erlangen, Germany.
authors.forename: Kristina
authors.initials: K
authors.lastname: Friedland
authors.affiliation: Department of Psychiatry and Psychotherapy, Friedrich-Alexander University Erlangen-Nürnberg , Schwabachanlage 6, 91054 Erlangen, Germany.
authors.forename: Christian P
authors.initials: CP
authors.lastname: Müller
authors.affiliation: Institute for Research in Immunology and Cancer (IRIC), Department of Biochemistry and Molecular Medicine, University of Montreal , Québec, Canada H3C 1J4.
authors.forename: Michel
authors.initials: M
authors.lastname: Bouvier
authors.affiliation: Department of Chemistry and Pharmacy, Medicinal Chemistry, Friedrich-Alexander University Erlangen-Nürnberg , Schuhstraße 19, 91052 Erlangen, Germany.
authors.forename: Peter
authors.identifier: 0000-0002-4127-197X
authors.initials: P
authors.lastname: Gmeiner
mesh_terms: D000818:Animals; D014150:Antipsychotic Agents / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use*; D018491:Dopamine Agonists / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use*; D055808:Drug Discovery; D019204:GTP-Binding Proteins / Q000378:metabolism; D006801:Humans; D008297:Male; D011720:Pyrazoles / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use*; D011725:Pyridines / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017448:Receptors, Dopamine D2 / Q000819:agonists* / Q000378:metabolism; D012559:Schizophrenia / Q000188:drug therapy* / Q000378:metabolism; D000071557:beta-Arrestins / Q000378:metabolism
chemical_list: D014150:Antipsychotic Agents; D018491:Dopamine Agonists; D011720:Pyrazoles; D011725:Pyridines; D017448:Receptors, Dopamine D2; D000071557:beta-Arrestins; C447480:pyrazolo(3,4-b)pyridine; D019204:GTP-Binding Proteins