Discovery of GPR183 Agonists Based on an Antagonist Scaffold
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Discovery of GPR183 Agonists Based on an Antagonist Scaffold. / Kjær, Viktoria M.S.; Ieremias, Loukas; Daugvilaite, Viktorija; Lückmann, Michael; Frimurer, Thomas M.; Ulven, Trond; Rosenkilde, Mette M.; Våbenø, Jon.
I: ChemMedChem, Bind 16, Nr. 17, 2021, s. 2623-2627.Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
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TY - JOUR
T1 - Discovery of GPR183 Agonists Based on an Antagonist Scaffold
AU - Kjær, Viktoria M.S.
AU - Ieremias, Loukas
AU - Daugvilaite, Viktorija
AU - Lückmann, Michael
AU - Frimurer, Thomas M.
AU - Ulven, Trond
AU - Rosenkilde, Mette M.
AU - Våbenø, Jon
N1 - Publisher Copyright: © 2021 The Authors. ChemMedChem published by Wiley-VCH GmbH
PY - 2021
Y1 - 2021
N2 - The G protein-coupled receptor GPR183/EBI2, which is activated by oxysterols, is a therapeutic target for inflammatory and metabolic diseases where both antagonists and agonists are of potential interest. Using the piperazine diamide core of the known GPR183 antagonist (E)-3-(4-bromophenyl)-1-(4-(4-methoxybenzoyl)piperazin-1-yl)prop-2-en-1-one (NIBR189) as starting point, we identified and sourced 79 structurally related compounds that were commercially available. In vitro screening of this compound collection using a Ca2+ mobilization assay resulted in the identification of 10 compounds with agonist properties. To enable establishment of initial structure-activity relationship trends, these were supplemented with five in-house compounds, two of which were also shown to be GPR183 agonists. Taken together, our findings suggest that the agonist activity of this compound series is dictated by the substitution pattern of one of the two distal phenyl rings, which functions as a molecular efficacy-switch.
AB - The G protein-coupled receptor GPR183/EBI2, which is activated by oxysterols, is a therapeutic target for inflammatory and metabolic diseases where both antagonists and agonists are of potential interest. Using the piperazine diamide core of the known GPR183 antagonist (E)-3-(4-bromophenyl)-1-(4-(4-methoxybenzoyl)piperazin-1-yl)prop-2-en-1-one (NIBR189) as starting point, we identified and sourced 79 structurally related compounds that were commercially available. In vitro screening of this compound collection using a Ca2+ mobilization assay resulted in the identification of 10 compounds with agonist properties. To enable establishment of initial structure-activity relationship trends, these were supplemented with five in-house compounds, two of which were also shown to be GPR183 agonists. Taken together, our findings suggest that the agonist activity of this compound series is dictated by the substitution pattern of one of the two distal phenyl rings, which functions as a molecular efficacy-switch.
KW - agonists
KW - antagonists
KW - drug discovery
KW - GPR183
KW - receptors
U2 - 10.1002/cmdc.202100301
DO - 10.1002/cmdc.202100301
M3 - Journal article
C2 - 34270165
AN - SCOPUS:85111685562
VL - 16
SP - 2623
EP - 2627
JO - Farmaco
JF - Farmaco
SN - 1860-7179
IS - 17
ER -
ID: 276333816