TY - JOUR
T1 - Design and Synthesis of 2,3- trans-Proline Analogues as Ligands for Ionotropic Glutamate Receptors and Excitatory Amino Acid Transporters
AU - Poulie, Christian B.M.
AU - Alcaide, Anna
AU - Krell-Jørgensen, Mikkel
AU - Larsen, Younes
AU - Astier, Eloi
AU - Bjørn-Yoshimoto, Walden E.
AU - Yi, Feng
AU - Syrenne, Jed T.
AU - Storgaard, Morten
AU - Nielsen, Birgitte
AU - Frydenvang, Karla A.
AU - Jensen, Anders A.
AU - Hansen, Kasper B.
AU - Pickering, Darryl S.
AU - Bunch, Lennart
N1 - Publisher Copyright:
© 2019 American Chemical Society.
PY - 2019/6/19
Y1 - 2019/6/19
N2 - Development of pharmacological tools for the ionotropic glutamate receptors (iGluRs) is imperative for the study and understanding of the role and function of these receptors in the central nervous system. We report the synthesis of 18 analogues of (2S,3R)-2-carboxy-3-pyrrolidine acetic acid (3a), which explores the effect of introducing a substituent on the ϵ-carbon (3c-q). A new synthetic method was developed for the efficient synthesis of racemic 3a and applied to give expedited access to 13 racemic analogues of 3a. Pharmacological characterization was carried out at native iGluRs, cloned homomeric kainate receptors (GluK1-3), NMDA receptors (GluN1/GluN2A-D), and excitatory amino acid transporters (EAAT1-3). From the structure-activity relationship studies, several new ligands emerged, exemplified by triazole 3p-d1, GluK3-preferring (GluK1/GluK3 Ki ratio of 15), and the structurally closely related tetrazole 3q-s3-4 that displayed 4.4-100-fold preference as an antagonist for the GluN1/GluN2A receptor (Ki = 0.61 μM) over GluN1/GluN2B-D (Ki = 2.7-62 μM).
AB - Development of pharmacological tools for the ionotropic glutamate receptors (iGluRs) is imperative for the study and understanding of the role and function of these receptors in the central nervous system. We report the synthesis of 18 analogues of (2S,3R)-2-carboxy-3-pyrrolidine acetic acid (3a), which explores the effect of introducing a substituent on the ϵ-carbon (3c-q). A new synthetic method was developed for the efficient synthesis of racemic 3a and applied to give expedited access to 13 racemic analogues of 3a. Pharmacological characterization was carried out at native iGluRs, cloned homomeric kainate receptors (GluK1-3), NMDA receptors (GluN1/GluN2A-D), and excitatory amino acid transporters (EAAT1-3). From the structure-activity relationship studies, several new ligands emerged, exemplified by triazole 3p-d1, GluK3-preferring (GluK1/GluK3 Ki ratio of 15), and the structurally closely related tetrazole 3q-s3-4 that displayed 4.4-100-fold preference as an antagonist for the GluN1/GluN2A receptor (Ki = 0.61 μM) over GluN1/GluN2B-D (Ki = 2.7-62 μM).
KW - CNS
KW - Glutamate receptors
KW - NMDA receptors
KW - kainate
KW - proline analogues
UR - http://www.scopus.com/inward/record.url?scp=85067426323&partnerID=8YFLogxK
U2 - 10.1021/acschemneuro.9b00205
DO - 10.1021/acschemneuro.9b00205
M3 - Article
C2 - 31124660
AN - SCOPUS:85067426323
SN - 1948-7193
VL - 10
SP - 2989
EP - 3007
JO - ACS Chemical Neuroscience
JF - ACS Chemical Neuroscience
IS - 6
ER -