Structure-guided development of dual β2 adrenergic/dopamine D2 receptor agonists

• Published in: Bioorganic & medicinal chemistry Vol. 24; no. 12; pp. 2641 - 2653
• Main Authors: Weichert, Dietmar, Stanek, Markus, Hübner, Harald, Gmeiner, Peter
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 15.06.2016
• Subjects: Adrenergic beta-2 Receptor Agonists - chemistry; Adrenergic beta-2 Receptor Agonists - pharmacology; Animals; Benzoxazines - chemistry; Benzoxazines - pharmacology; CHO Cells; Cricetulus; Dopamine Agonists - chemistry; Dopamine Agonists - pharmacology; Dopamine receptor; Drug Discovery; G protein-coupled receptors; HEK293 Cells; Humans; Models, Molecular; Molecular probes; Neurodegenerative disorders; Parkinson Disease - drug therapy; Parkinson Disease - metabolism; Parkinson’s disease; Polypharmacology; Receptors, Adrenergic, beta-2 - metabolism; Receptors, Dopamine D2 - agonists; Receptors, Dopamine D2 - metabolism; β2 adrenergic receptor; G protein-coupled receptors; Dopamine receptor; Polypharmacology; Molecular probes; β2 adrenergic receptor; Neurodegenerative disorders; Parkinson’s disease; β adrenergic receptor
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2016.04.028

[Display omitted] 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.