Weichert D, Stanek M, Hübner H, Gmeiner P (2016)
Publication Language: English
Publication Status: Published
Publication Type: Journal article, Original article
Publication year: 2016
Publisher: Elsevier
Book Volume: 24
Pages Range: 2641-2653
DOI: 10.1016/j.bmc.2016.04.028
Aiming to discover dual-acting beta(2) adrenergic/dopamine D-2 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 beta(2) receptor and substantial G protein-promoted activation at the D-2 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 beta(2) adrenergic antagonist/D-2 receptor agonist with K-i values in the low nanomolar range. The compounds may serve as a promising starting point for the investigation and treatment of neurological disorders. (C) 2016 Elsevier Ltd. All rights reserved.
APA:
Weichert, D., Stanek, M., Hübner, H., & Gmeiner, P. (2016). Structure-guided development of dual ß2 adrenergic/dopamine D-2 receptor agonists. Bioorganic & Medicinal Chemistry, 24, 2641-2653. https://dx.doi.org/10.1016/j.bmc.2016.04.028
MLA:
Weichert, Dietmar, et al. "Structure-guided development of dual ß2 adrenergic/dopamine D-2 receptor agonists." Bioorganic & Medicinal Chemistry 24 (2016): 2641-2653.
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