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

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

Author information

1
Department of Chemistry and Pharmacy, Medicinal Chemistry, Emil Fischer Center, Friedrich-Alexander University, Schuhstraße 19, 91052 Erlangen, Germany.
2
Department of Chemistry and Pharmacy, Medicinal Chemistry, Emil Fischer Center, Friedrich-Alexander University, Schuhstraße 19, 91052 Erlangen, Germany. Electronic address: peter.gmeiner@fau.de.

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.

KEYWORDS:

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

PMID:
27132867
DOI:
10.1016/j.bmc.2016.04.028
[Indexed for MEDLINE]

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