title: Structure-guided development of dual β2 adrenergic/dopamine D2 receptor agonists.
abstract: Aiming to discover dual-acting β2 adrenergic/dopamine D2 receptor ligands, a structure-guided approach for the evolution of GPCR agonists that address multiple targets was elaborated. Starting from GPCR crystal structures, we describe the design, synthesis and biological investigation of a defined set of compounds leading to the identification of the benzoxazinone (R)-3, which shows agonist properties at the adrenergic β2 receptor and substantial G protein-promoted activation at the D2 receptor. This directed approach yielded molecular probes with tuned dual activity. The congener desOH-3 devoid of the benzylic hydroxyl function was shown to be a β2 adrenergic antagonist/D2 receptor agonist with Ki values in the low nanomolar range. The compounds may serve as a promising starting point for the investigation and treatment of neurological disorders.
authors.affiliation: Department of Chemistry and Pharmacy, Medicinal Chemistry, Emil Fischer Center, Friedrich-Alexander University, Schuhstraße 19, 91052 Erlangen, Germany.
authors.forename: Dietmar
authors.initials: D
authors.lastname: Weichert
authors.affiliation: Department of Chemistry and Pharmacy, Medicinal Chemistry, Emil Fischer Center, Friedrich-Alexander University, Schuhstraße 19, 91052 Erlangen, Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: Stanek
authors.affiliation: Department of Chemistry and Pharmacy, Medicinal Chemistry, Emil Fischer Center, Friedrich-Alexander University, Schuhstraße 19, 91052 Erlangen, Germany.
authors.forename: Harald
authors.initials: H
authors.lastname: Hübner
authors.affiliation: Department of Chemistry and Pharmacy, Medicinal Chemistry, Emil Fischer Center, Friedrich-Alexander University, Schuhstraße 19, 91052 Erlangen, Germany. Electronic address: peter.gmeiner@fau.de.
authors.forename: Peter
authors.initials: P
authors.lastname: Gmeiner
mesh_terms: D058666:Adrenergic beta-2 Receptor Agonists / Q000737:chemistry* / Q000494:pharmacology*; D000818:Animals; D048588:Benzoxazines / Q000737:chemistry* / Q000494:pharmacology*; D016466:CHO Cells; D003412:Cricetulus; D018491:Dopamine Agonists / Q000737:chemistry* / Q000494:pharmacology*; D055808:Drug Discovery; D057809:HEK293 Cells; D006801:Humans; D008958:Models, Molecular; D010300:Parkinson Disease / Q000188:drug therapy / Q000378:metabolism; D064798:Polypharmacology; D018343:Receptors, Adrenergic, beta-2 / Q000378:metabolism; D017448:Receptors, Dopamine D2 / Q000819:agonists* / Q000378:metabolism
chemical_list: D058666:Adrenergic beta-2 Receptor Agonists; D048588:Benzoxazines; D018491:Dopamine Agonists; D018343:Receptors, Adrenergic, beta-2; D017448:Receptors, Dopamine D2
keywords: Dopamine receptor; G protein-coupled receptors; Molecular probes; Neurodegenerative disorders; Parkinson’s disease; Polypharmacology; β(2) adrenergic receptor