Structure-guided development of dual β2 adrenergic/dopamine D2 receptor agonists.
Basic Information
ID: ALA3797035
Journal: Bioorg Med Chem
Title: Structure-guided development of dual β2 adrenergic/dopamine D2 receptor agonists.
Authors: Weichert D, Stanek M, Hübner H, Gmeiner P.
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.
CiteXplore: 27132867
DOI: 10.1016/j.bmc.2016.04.028
Patent ID: ┄