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

Bioorg Med Chem. 2016 Jun 15;24(12):2641-53. doi: 10.1016/j.bmc.2016.04.028. Epub 2016 Apr 19.


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.

Keywords: Dopamine receptor; G protein-coupled receptors; Molecular probes; Neurodegenerative disorders; Parkinson’s disease; Polypharmacology; β(2) adrenergic receptor.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 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*
  • Drug Discovery
  • HEK293 Cells
  • Humans
  • Models, Molecular
  • Parkinson Disease / drug therapy
  • Parkinson Disease / metabolism
  • Polypharmacology
  • Receptors, Adrenergic, beta-2 / metabolism
  • Receptors, Dopamine D2 / agonists*
  • Receptors, Dopamine D2 / metabolism


  • Adrenergic beta-2 Receptor Agonists
  • Benzoxazines
  • Dopamine Agonists
  • Receptors, Adrenergic, beta-2
  • Receptors, Dopamine D2