PMID- 32538088
OWN - NLM
STAT- MEDLINE
DCOM- 20201207
LR  - 20210724
IS  - 1520-4804 (Electronic)
IS  - 0022-2623 (Print)
IS  - 0022-2623 (Linking)
VI  - 63
IP  - 14
DP  - 2020 Jul 23
TI  - Discovery of Dihydropyrrolo[1,2-a]pyrazin-3(4H)-one-Based Second-Generation 
      GluN2C- and GluN2D-Selective Positive Allosteric Modulators (PAMs) of the 
      N-Methyl-d-Aspartate (NMDA) Receptor.
PG  - 7569-7600
LID - 10.1021/acs.jmedchem.9b01733 [doi]
AB  - The N-methyl-d-aspartate receptor (NMDAR) is an ion channel that mediates the 
      slow, Ca(2+)-permeable component of glutamatergic synaptic transmission in the 
      central nervous system (CNS). NMDARs are known to play a significant role in 
      basic neurological functions, and their dysfunction has been implicated in 
      several CNS disorders. Herein, we report the discovery of second-generation 
      GluN2C/D-selective NMDAR-positive allosteric modulators (PAMs) with a 
      dihydropyrrolo[1,2-a]pyrazin-3(4H)-one core. The prototype, R-(+)-EU-1180-453, 
      exhibits log unit improvements in the concentration needed to double receptor 
      response, lipophilic efficiency, and aqueous solubility, and lowers cLogP by one 
      log unit compared to the first-generation prototype CIQ. Additionally, 
      R-(+)-EU-1180-453 was found to increase glutamate potency 2-fold, increase the 
      response to maximally effective concentration of agonist 4-fold, and the racemate 
      is brain-penetrant. These compounds are useful second-generation in vitro tools 
      and a promising step toward in vivo tools for the study of positive modulation of 
      GluN2C- and GluN2D-containing NMDA receptors.
FAU - Epplin, Matthew P
AU  - Epplin MP
AUID- ORCID: 0000-0002-1121-3701
AD  - Department of Chemistry, Emory University, 1515 Dickey Drive, Atlanta, Georgia 
      30322, United States.
FAU - Mohan, Ayush
AU  - Mohan A
AD  - Department of Chemistry, Emory University, 1515 Dickey Drive, Atlanta, Georgia 
      30322, United States.
FAU - Harris, Lynnea D
AU  - Harris LD
AD  - Department of Chemistry, Emory University, 1515 Dickey Drive, Atlanta, Georgia 
      30322, United States.
FAU - Zhu, Zongjian
AU  - Zhu Z
AD  - Department of Pharmacology and Chemical Biology, Emory University, 1510 Clifton 
      Road, Atlanta, Georgia 30322, United States.
FAU - Strong, Katie L
AU  - Strong KL
AD  - Department of Chemistry, Emory University, 1515 Dickey Drive, Atlanta, Georgia 
      30322, United States.
FAU - Bacsa, John
AU  - Bacsa J
AUID- ORCID: 0000-0001-5681-4458
AD  - Department of Chemistry, Emory University, 1515 Dickey Drive, Atlanta, Georgia 
      30322, United States.
FAU - Le, Phuong
AU  - Le P
AD  - Department of Pharmacology and Chemical Biology, Emory University, 1510 Clifton 
      Road, Atlanta, Georgia 30322, United States.
FAU - Menaldino, David S
AU  - Menaldino DS
AD  - Department of Chemistry, Emory University, 1515 Dickey Drive, Atlanta, Georgia 
      30322, United States.
FAU - Traynelis, Stephen F
AU  - Traynelis SF
AUID- ORCID: 0000-0002-3750-9615
AD  - Department of Pharmacology and Chemical Biology, Emory University, 1510 Clifton 
      Road, Atlanta, Georgia 30322, United States.
FAU - Liotta, Dennis C
AU  - Liotta DC
AUID- ORCID: 0000-0002-7736-7113
AD  - Department of Chemistry, Emory University, 1515 Dickey Drive, Atlanta, Georgia 
      30322, United States.
LA  - eng
GR  - R01 NS065371/NS/NINDS NIH HHS/United States
GR  - R35 NS111619/NS/NINDS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20200706
PL  - United States
TA  - J Med Chem
JT  - Journal of medicinal chemistry
JID - 9716531
RN  - 0 (Isoquinolines)
RN  - 0 (NR2C NMDA receptor)
RN  - 0 (NR2D NMDA receptor)
RN  - 0 (Pyrazines)
RN  - 0 (Pyrroles)
RN  - 0 (Receptors, N-Methyl-D-Aspartate)
SB  - IM
MH  - Allosteric Regulation
MH  - Animals
MH  - Drug Design
MH  - Isoquinolines/chemical synthesis/pharmacology
MH  - Male
MH  - Mice, Inbred C57BL
MH  - Molecular Structure
MH  - Pyrazines/chemical synthesis/pharmacokinetics/*pharmacology
MH  - Pyrroles/chemical synthesis/pharmacokinetics/*pharmacology
MH  - Receptors, N-Methyl-D-Aspartate/*agonists
MH  - Structure-Activity Relationship
MH  - Xenopus laevis
PMC - PMC7961853
MID - NIHMS1678890
COIS- The authors declare the following competing financial interest(s): SFT is a PI on 
      research grants from Allergan, Biogen, and Janssen to Emory, is a member of the 
      SAB for Sage Therapeutics, the GRIN2B Foundation, CureGRIN Foundation, is a 
      co-founder of NeurOp Inc and AgriThera, and receives licensing fees and royalties 
      for software. DCL is a member of the Board of Directors for NeurOp Inc and 
      co-founder of AgriThera. DCL, DSM, KLS, MPE, SFT are co-inventors on Emory-owned 
      Intellectual Property that includes positive allosteric modulators of NMDA 
      receptor function.
EDAT- 2020/06/17 06:00
MHDA- 2020/12/15 06:00
PMCR- 2021/07/23
CRDT- 2020/06/16 06:00
PHST- 2020/06/17 06:00 [pubmed]
PHST- 2020/12/15 06:00 [medline]
PHST- 2020/06/16 06:00 [entrez]
PHST- 2021/07/23 00:00 [pmc-release]
AID - 10.1021/acs.jmedchem.9b01733 [doi]
PST - ppublish
SO  - J Med Chem. 2020 Jul 23;63(14):7569-7600. doi: 10.1021/acs.jmedchem.9b01733. Epub 
      2020 Jul 6.