Enhancing Action of Positive Allosteric Modulators through the Design of Dimeric Compounds
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Enhancing Action of Positive Allosteric Modulators through the Design of Dimeric Compounds. / Drapier, Thomas; Geubelle, Pierre; Bouckaert, Charlotte; Nielsen, Lise; Laulumaa, Saara; Goffin, Eric; Dilly, Sébastien; Francotte, Pierre; Hanson, Julien; Pochet, Lionel; Kastrup, Jette Sandholm; Pirotte, Bernard.
In: Journal of Medicinal Chemistry, Vol. 61, No. 12, 28.06.2018, p. 5279-5291.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - Enhancing Action of Positive Allosteric Modulators through the Design of Dimeric Compounds
AU - Drapier, Thomas
AU - Geubelle, Pierre
AU - Bouckaert, Charlotte
AU - Nielsen, Lise
AU - Laulumaa, Saara
AU - Goffin, Eric
AU - Dilly, Sébastien
AU - Francotte, Pierre
AU - Hanson, Julien
AU - Pochet, Lionel
AU - Kastrup, Jette Sandholm
AU - Pirotte, Bernard
PY - 2018/6/28
Y1 - 2018/6/28
N2 - The present study describes the identification of highly potent dimeric 1,2,4-benzothiadiazine 1,1-dioxide (BTD)-type positive allosteric modulators of the AMPA receptors (AMPApams) obtained by linking two monomeric BTD scaffolds through their respective 6-positions. Using previous X-ray data from monomeric BTDs cocrystallized with the GluA2 ligand-binding domain (LBD), a molecular modeling approach was performed to predict the preferred dimeric combinations. Two 6,6-ethylene-linked dimeric BTD compounds (16 and 22) were prepared and evaluated as AMPApams on HEK293 cells expressing GluA2o( Q) (calcium flux experiment). These compounds were found to be about 10,000 times more potent than their respective monomers, the most active dimeric compound being the bis-4-cyclopropyl-substituted compound 22 [6,6'-(ethane-1,2-diyl)bis(4-cyclopropyl-3,4-dihydro-2 H-1,2,4-benzothiadiazine 1,1-dioxide], with an EC50 value of 1.4 nM. As a proof of concept, the bis-4-methyl-substituted dimeric compound 16 (EC50 = 13 nM) was successfully cocrystallized with the GluA2o-LBD and was found to occupy the two BTD binding sites at the LBD dimer interface.
AB - The present study describes the identification of highly potent dimeric 1,2,4-benzothiadiazine 1,1-dioxide (BTD)-type positive allosteric modulators of the AMPA receptors (AMPApams) obtained by linking two monomeric BTD scaffolds through their respective 6-positions. Using previous X-ray data from monomeric BTDs cocrystallized with the GluA2 ligand-binding domain (LBD), a molecular modeling approach was performed to predict the preferred dimeric combinations. Two 6,6-ethylene-linked dimeric BTD compounds (16 and 22) were prepared and evaluated as AMPApams on HEK293 cells expressing GluA2o( Q) (calcium flux experiment). These compounds were found to be about 10,000 times more potent than their respective monomers, the most active dimeric compound being the bis-4-cyclopropyl-substituted compound 22 [6,6'-(ethane-1,2-diyl)bis(4-cyclopropyl-3,4-dihydro-2 H-1,2,4-benzothiadiazine 1,1-dioxide], with an EC50 value of 1.4 nM. As a proof of concept, the bis-4-methyl-substituted dimeric compound 16 (EC50 = 13 nM) was successfully cocrystallized with the GluA2o-LBD and was found to occupy the two BTD binding sites at the LBD dimer interface.
U2 - 10.1021/acs.jmedchem.8b00250
DO - 10.1021/acs.jmedchem.8b00250
M3 - Journal article
C2 - 29775064
VL - 61
SP - 5279
EP - 5291
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
SN - 0022-2623
IS - 12
ER -
ID: 199337651