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

Männel B, Hübner H, Möller D, Gmeiner P (2017)


Publication Status: Published

Publication Type: Journal article, Original article

Publication year: 2017

Journal

Publisher: PERGAMON-ELSEVIER SCIENCE LTD

Book Volume: 25

Pages Range: 5613-5628

Journal Issue: 20

DOI: 10.1016/j.bmc.2017.08.037

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.

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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.

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