TY - JOUR
T1 - Distinct GluN1 and GluN2 Structural Determinants for Subunit-Selective Positive Allosteric Modulation of N-Methyl-d-aspartate Receptors
AU - Strong, Katie L.
AU - Epplin, Matthew P.
AU - Ogden, Kevin K.
AU - Burger, Pieter B.
AU - Kaiser, Thomas M.
AU - Wilding, Timothy J.
AU - Kusumoto, Hiro
AU - Camp, Chad R.
AU - Shaulsky, Gil
AU - Bhattacharya, Subhrajit
AU - Perszyk, Riley E.
AU - Menaldino, David S.
AU - McDaniel, Miranda J.
AU - Zhang, Jing
AU - Le, Phuong
AU - Banke, Tue G.
AU - Hansen, Kasper B.
AU - Huettner, James E.
AU - Liotta, Dennis C.
AU - Traynelis, Stephen F.
N1 - Funding Information:
This work was supported by the NINDS (NS NS065371, NS111619 to S.F.T.; NS30888 to J.E.H.; GM103546, NS097536 to K.B.H.) and a research grant from Janssen Pharmaceuticals, Inc. (S.F.T.).
Funding Information:
The authors declare the following competing financial interest(s): S.F.T. is a consultant for Janssen Pharmaceuticals Inc., is PI on research grants from Allergan, Biogen, and Janssen to Emory, is a member of the SAB for Eumentis Inc. and Sage Therapeutics, is co-founder of NeurOp Inc, and has received licensing fees and royalties from Emory. D.C.L. is a member of the Board of Directors for NeurOp Inc. D.C.L., D.S.M., K.L.S., M.P.E., and S.F.T. are co-inventors on Emory-owned Intellectual Property that includes positive allosteric modulators of NMDA receptor function. K.B.H. is PI on a research grant from Janssen Research and Development to University of Montana. Acknowledgments
Publisher Copyright:
© 2021 American Chemical Society. All rights reserved.
PY - 2021/1/6
Y1 - 2021/1/6
N2 - N-Methyl-d-aspartate receptors (NMDARs) are ionotropic ligand-gated glutamate receptors that mediate fast excitatory synaptic transmission in the central nervous system (CNS). Several neurological disorders may involve NMDAR hypofunction, which has driven therapeutic interest in positive allosteric modulators (PAMs) of NMDAR function. Here we describe modest changes to the tetrahydroisoquinoline scaffold of GluN2C/GluN2D-selective PAMs that expands activity to include GluN2A- A nd GluN2B-containing recombinant and synaptic NMDARs. These new analogues are distinct from GluN2C/GluN2D-selective compounds like (+)-(3-chlorophenyl)(6,7-dimethoxy-1-((4-methoxyphenoxy)methyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone (CIQ) by virtue of their subunit selectivity, molecular determinants of action, and allosteric regulation of agonist potency. The (S)-enantiomers of two analogues (EU1180-55, EU1180-154) showed activity at NMDARs containing all subunits (GluN2A, GluN2B, GluN2C, GluN2D), whereas the (R)-enantiomers were primarily active at GluN2C- A nd GluN2D-containing NMDARs. Determination of the actions of enantiomers on triheteromeric receptors confirms their unique pharmacology, with greater activity of (S) enantiomers at GluN2A/GluN2D and GluN2B/GluN2D subunit combinations than (R) enantiomers. Evaluation of the (S)-EU1180-55 and EU1180-154 response of chimeric kainate/NMDA receptors revealed structural determinants of action within the pore-forming region and associated linkers. Scanning mutagenesis identified structural determinants within the GluN1 pre-M1 and M1 regions that alter the activity of (S)-EU1180-55 but not (R)-EU1180-55. By contrast, mutations in pre-M1 and M1 regions of GluN2D perturb the actions of only the (R)-EU1180-55 but not the (S) enantiomer. Molecular modeling supports the idea that the (S) and (R) enantiomers interact distinctly with GluN1 and GluN2 pre-M1 regions, suggesting that two distinct sites exist for these NMDAR PAMs, each of which has different functional effects.
AB - N-Methyl-d-aspartate receptors (NMDARs) are ionotropic ligand-gated glutamate receptors that mediate fast excitatory synaptic transmission in the central nervous system (CNS). Several neurological disorders may involve NMDAR hypofunction, which has driven therapeutic interest in positive allosteric modulators (PAMs) of NMDAR function. Here we describe modest changes to the tetrahydroisoquinoline scaffold of GluN2C/GluN2D-selective PAMs that expands activity to include GluN2A- A nd GluN2B-containing recombinant and synaptic NMDARs. These new analogues are distinct from GluN2C/GluN2D-selective compounds like (+)-(3-chlorophenyl)(6,7-dimethoxy-1-((4-methoxyphenoxy)methyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone (CIQ) by virtue of their subunit selectivity, molecular determinants of action, and allosteric regulation of agonist potency. The (S)-enantiomers of two analogues (EU1180-55, EU1180-154) showed activity at NMDARs containing all subunits (GluN2A, GluN2B, GluN2C, GluN2D), whereas the (R)-enantiomers were primarily active at GluN2C- A nd GluN2D-containing NMDARs. Determination of the actions of enantiomers on triheteromeric receptors confirms their unique pharmacology, with greater activity of (S) enantiomers at GluN2A/GluN2D and GluN2B/GluN2D subunit combinations than (R) enantiomers. Evaluation of the (S)-EU1180-55 and EU1180-154 response of chimeric kainate/NMDA receptors revealed structural determinants of action within the pore-forming region and associated linkers. Scanning mutagenesis identified structural determinants within the GluN1 pre-M1 and M1 regions that alter the activity of (S)-EU1180-55 but not (R)-EU1180-55. By contrast, mutations in pre-M1 and M1 regions of GluN2D perturb the actions of only the (R)-EU1180-55 but not the (S) enantiomer. Molecular modeling supports the idea that the (S) and (R) enantiomers interact distinctly with GluN1 and GluN2 pre-M1 regions, suggesting that two distinct sites exist for these NMDAR PAMs, each of which has different functional effects.
KW - EPSC
KW - Electrophysiology
KW - molecular dynamics
KW - positive allosteric modulator
UR - http://www.scopus.com/inward/record.url?scp=85099034913&partnerID=8YFLogxK
U2 - 10.1021/acschemneuro.0c00561
DO - 10.1021/acschemneuro.0c00561
M3 - Article
C2 - 33326224
AN - SCOPUS:85099034913
SN - 1948-7193
VL - 12
SP - 79
EP - 98
JO - ACS Chemical Neuroscience
JF - ACS Chemical Neuroscience
IS - 1
ER -