beta-Arrestin biased dopamine D2 receptor partial agonists: Synthesis and pharmacological evaluation

Journal article
(Original article)


Publication Details

Author(s): Männel B, Hübner H, Möller D, Gmeiner P
Journal: Bioorganic & Medicinal Chemistry
Publisher: PERGAMON-ELSEVIER SCIENCE LTD
Publication year: 2017
Volume: 25
Journal issue: 20
Pages range: 5613-5628
ISSN: 0968-0896


Abstract


beta-Arrestin biased G protein-coupled receptor ligands represent important molecular probes and may increase favorable drug action and safety as novel therapeutics. Starting from recently discovered hydroxy-substituted heterocyclic piperazine scaffolds, we have developed a series of dopamine D-2 receptor ligands with a pyrazolo[1,5-a]pyridine as secondary pharmacophore that is functionalized in position 3 by a formyl or hydroxyiminomethyl substituent. The ligands, especially the benzoxazinone 9d, were found to stimulate substantial beta-arrestin-2 recruitment, while being nearly devoid of activity in a GTP gamma S binding assay. Investigating a new series of truncated analogs lacking a secondary pharmacophore, considerable b-arrestin-2 recruitment in the absence of G protein activation was found, when a 5-hydroxy-2H-benzo[b][1,4]oxazin-3(4H)-one was combined with an N-propyl-substituted 1,4-diazepane (15c). Although 15c displayed reduced potency compared to 9d, the dose-response curves indicate that a hydroxy-substituted heterocyclic primary pharmacophore is sufficient for the functionally selective activation of D2R. (C) 2017 Elsevier Ltd. All rights reserved.



FAU Authors / FAU Editors

Gmeiner, Peter Prof. Dr.
Lehrstuhl für Pharmazeutische Chemie
Hübner, Harald Dr.
Lehrstuhl für Pharmazeutische Chemie
Männel, Barbara
Lehrstuhl für Pharmazeutische Chemie
Weikert, Dorothee Dr.
Lehrstuhl für Pharmazeutische Chemie


Additional Organisation
Emil-Fischer-Zentrum (Emil Fischer Center)


How to cite

APA:
Männel, B., Hübner, H., Möller, D., & Gmeiner, P. (2017). beta-Arrestin biased dopamine D2 receptor partial agonists: Synthesis and pharmacological evaluation. Bioorganic & Medicinal Chemistry, 25(20), 5613-5628. https://dx.doi.org/10.1016/j.bmc.2017.08.037

MLA:
Männel, Barbara, et al. "beta-Arrestin biased dopamine D2 receptor partial agonists: Synthesis and pharmacological evaluation." Bioorganic & Medicinal Chemistry 25.20 (2017): 5613-5628.

BibTeX: 

Last updated on 2018-10-08 at 23:55