PMID- 34493631
OWN - NLM
STAT- MEDLINE
DCOM- 20211230
LR  - 20221003
IS  - 1521-0103 (Electronic)
IS  - 0022-3565 (Print)
IS  - 0022-3565 (Linking)
VI  - 379
IP  - 1
DP  - 2021 Oct
TI  - A Glutamate N-Methyl-d-Aspartate (NMDA) Receptor Subunit 2B-Selective Inhibitor 
      of NMDA Receptor Function with Enhanced Potency at Acidic pH and Oral 
      Bioavailability for Clinical Use.
PG  - 41-52
LID - 10.1124/jpet.120.000370 [doi]
AB  - We describe a clinical candidate molecule from a new series of glutamate 
      N-methyl-d-aspartate receptor subunit 2B-selective inhibitors that shows enhanced 
      inhibition at extracellular acidic pH values relative to physiologic pH. This 
      property should render these compounds more effective inhibitors of 
      N-methyl-d-aspartate receptors at synapses responding to a high frequency of 
      action potentials, since glutamate-containing vesicles are acidic within their 
      lumen. In addition, acidification of penumbral regions around ischemic tissue 
      should also enhance selective drug action for improved neuroprotection. The aryl 
      piperazine we describe here shows strong neuroprotective actions with minimal 
      side effects in preclinical studies. The clinical candidate molecule NP10679 has 
      high oral bioavailability with good brain penetration and is suitable for both 
      intravenous and oral dosing for therapeutic use in humans. SIGNIFICANCE 
      STATEMENT: This study identifies a new series of glutamate N-methyl-d-aspartate 
      (NMDA) receptor subunit 2B-selective negative allosteric modulators with 
      properties appropriate for clinical advancement. The compounds are more potent at 
      acidic pH, associated with ischemic tissue, and this property should increase the 
      therapeutic safety of this class by improving efficacy in affected tissue while 
      sparing NMDA receptor block in healthy brain.
CI  - Copyright (c) 2021 by The American Society for Pharmacology and Experimental 
      Therapeutics.
FAU - Myers, Scott J
AU  - Myers SJ
AD  - Department of Pharmacology and Chemical Biology (S.J.M, P.L., R.J.D., S.F.T.), 
      Department of Chemistry (L.J.W., Y.A.T., D.S.M., Z.W.D., D.C.L.), Emory 
      University, Atlanta, Georgia; NeurOp Inc., Atlanta, Georgia (S.J.M., K.P.R., 
      L.J.W., Y.A.T, P.L., D.S.M., Z.W.D., G.W.K., R.Z.), and TRPblue Inc., Durham, 
      North Carolina (G.W.K).
FAU - Ruppa, Kamalesh P
AU  - Ruppa KP
AD  - Department of Pharmacology and Chemical Biology (S.J.M, P.L., R.J.D., S.F.T.), 
      Department of Chemistry (L.J.W., Y.A.T., D.S.M., Z.W.D., D.C.L.), Emory 
      University, Atlanta, Georgia; NeurOp Inc., Atlanta, Georgia (S.J.M., K.P.R., 
      L.J.W., Y.A.T, P.L., D.S.M., Z.W.D., G.W.K., R.Z.), and TRPblue Inc., Durham, 
      North Carolina (G.W.K).
FAU - Wilson, Lawrence J
AU  - Wilson LJ
AD  - Department of Pharmacology and Chemical Biology (S.J.M, P.L., R.J.D., S.F.T.), 
      Department of Chemistry (L.J.W., Y.A.T., D.S.M., Z.W.D., D.C.L.), Emory 
      University, Atlanta, Georgia; NeurOp Inc., Atlanta, Georgia (S.J.M., K.P.R., 
      L.J.W., Y.A.T, P.L., D.S.M., Z.W.D., G.W.K., R.Z.), and TRPblue Inc., Durham, 
      North Carolina (G.W.K).
FAU - Tahirovic, Yesim A
AU  - Tahirovic YA
AD  - Department of Pharmacology and Chemical Biology (S.J.M, P.L., R.J.D., S.F.T.), 
      Department of Chemistry (L.J.W., Y.A.T., D.S.M., Z.W.D., D.C.L.), Emory 
      University, Atlanta, Georgia; NeurOp Inc., Atlanta, Georgia (S.J.M., K.P.R., 
      L.J.W., Y.A.T, P.L., D.S.M., Z.W.D., G.W.K., R.Z.), and TRPblue Inc., Durham, 
      North Carolina (G.W.K).
FAU - Lyuboslavsky, Polina
AU  - Lyuboslavsky P
AD  - Department of Pharmacology and Chemical Biology (S.J.M, P.L., R.J.D., S.F.T.), 
      Department of Chemistry (L.J.W., Y.A.T., D.S.M., Z.W.D., D.C.L.), Emory 
      University, Atlanta, Georgia; NeurOp Inc., Atlanta, Georgia (S.J.M., K.P.R., 
      L.J.W., Y.A.T, P.L., D.S.M., Z.W.D., G.W.K., R.Z.), and TRPblue Inc., Durham, 
      North Carolina (G.W.K).
FAU - Menaldino, David S
AU  - Menaldino DS
AD  - Department of Pharmacology and Chemical Biology (S.J.M, P.L., R.J.D., S.F.T.), 
      Department of Chemistry (L.J.W., Y.A.T., D.S.M., Z.W.D., D.C.L.), Emory 
      University, Atlanta, Georgia; NeurOp Inc., Atlanta, Georgia (S.J.M., K.P.R., 
      L.J.W., Y.A.T, P.L., D.S.M., Z.W.D., G.W.K., R.Z.), and TRPblue Inc., Durham, 
      North Carolina (G.W.K).
FAU - Dentmon, Zackery W
AU  - Dentmon ZW
AD  - Department of Pharmacology and Chemical Biology (S.J.M, P.L., R.J.D., S.F.T.), 
      Department of Chemistry (L.J.W., Y.A.T., D.S.M., Z.W.D., D.C.L.), Emory 
      University, Atlanta, Georgia; NeurOp Inc., Atlanta, Georgia (S.J.M., K.P.R., 
      L.J.W., Y.A.T, P.L., D.S.M., Z.W.D., G.W.K., R.Z.), and TRPblue Inc., Durham, 
      North Carolina (G.W.K).
FAU - Koszalka, George W
AU  - Koszalka GW
AD  - Department of Pharmacology and Chemical Biology (S.J.M, P.L., R.J.D., S.F.T.), 
      Department of Chemistry (L.J.W., Y.A.T., D.S.M., Z.W.D., D.C.L.), Emory 
      University, Atlanta, Georgia; NeurOp Inc., Atlanta, Georgia (S.J.M., K.P.R., 
      L.J.W., Y.A.T, P.L., D.S.M., Z.W.D., G.W.K., R.Z.), and TRPblue Inc., Durham, 
      North Carolina (G.W.K).
FAU - Zaczek, Robert
AU  - Zaczek R
AD  - Department of Pharmacology and Chemical Biology (S.J.M, P.L., R.J.D., S.F.T.), 
      Department of Chemistry (L.J.W., Y.A.T., D.S.M., Z.W.D., D.C.L.), Emory 
      University, Atlanta, Georgia; NeurOp Inc., Atlanta, Georgia (S.J.M., K.P.R., 
      L.J.W., Y.A.T, P.L., D.S.M., Z.W.D., G.W.K., R.Z.), and TRPblue Inc., Durham, 
      North Carolina (G.W.K).
FAU - Dingledine, Raymond J
AU  - Dingledine RJ
AD  - Department of Pharmacology and Chemical Biology (S.J.M, P.L., R.J.D., S.F.T.), 
      Department of Chemistry (L.J.W., Y.A.T., D.S.M., Z.W.D., D.C.L.), Emory 
      University, Atlanta, Georgia; NeurOp Inc., Atlanta, Georgia (S.J.M., K.P.R., 
      L.J.W., Y.A.T, P.L., D.S.M., Z.W.D., G.W.K., R.Z.), and TRPblue Inc., Durham, 
      North Carolina (G.W.K).
FAU - Traynelis, Stephen F
AU  - Traynelis SF
AD  - Department of Pharmacology and Chemical Biology (S.J.M, P.L., R.J.D., S.F.T.), 
      Department of Chemistry (L.J.W., Y.A.T., D.S.M., Z.W.D., D.C.L.), Emory 
      University, Atlanta, Georgia; NeurOp Inc., Atlanta, Georgia (S.J.M., K.P.R., 
      L.J.W., Y.A.T, P.L., D.S.M., Z.W.D., G.W.K., R.Z.), and TRPblue Inc., Durham, 
      North Carolina (G.W.K) strayne@emory.edu.
FAU - Liotta, Dennis C
AU  - Liotta DC
AD  - Department of Pharmacology and Chemical Biology (S.J.M, P.L., R.J.D., S.F.T.), 
      Department of Chemistry (L.J.W., Y.A.T., D.S.M., Z.W.D., D.C.L.), Emory 
      University, Atlanta, Georgia; NeurOp Inc., Atlanta, Georgia (S.J.M., K.P.R., 
      L.J.W., Y.A.T, P.L., D.S.M., Z.W.D., G.W.K., R.Z.), and TRPblue Inc., Durham, 
      North Carolina (G.W.K).
LA  - eng
GR  - R44 NS071657/NS/NINDS NIH HHS/United States
GR  - R43 NS049666/NS/NINDS NIH HHS/United States
GR  - U44 NS071657/NS/NINDS NIH HHS/United States
GR  - R44 NS049666/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
PT  - Research Support, Non-U.S. Gov't
DEP - 20210907
PL  - United States
TA  - J Pharmacol Exp Ther
JT  - The Journal of pharmacology and experimental therapeutics
JID - 0376362
RN  - 0 (Acids)
RN  - 0 (Excitatory Amino Acid Antagonists)
RN  - 0 (NR2B NMDA receptor)
RN  - 0 (Receptors, N-Methyl-D-Aspartate)
SB  - IM
MH  - Acids
MH  - Administration, Oral
MH  - Animals
MH  - Biological Availability
MH  - Brain/*drug effects/*metabolism
MH  - Dose-Response Relationship, Drug
MH  - Excitatory Amino Acid Antagonists/*administration & dosage/*metabolism
MH  - Female
MH  - Hydrogen-Ion Concentration
MH  - Male
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Receptors, N-Methyl-D-Aspartate/*antagonists & inhibitors/*metabolism
MH  - Xenopus laevis
PMC - PMC8626636
EDAT- 2021/09/09 06:00
MHDA- 2021/12/31 06:00
PMCR- 2022/10/01
CRDT- 2021/09/08 06:15
PHST- 2020/10/10 00:00 [received]
PHST- 2021/04/02 00:00 [accepted]
PHST- 2021/09/09 06:00 [pubmed]
PHST- 2021/12/31 06:00 [medline]
PHST- 2021/09/08 06:15 [entrez]
PHST- 2022/10/01 00:00 [pmc-release]
AID - jpet.120.000370 [pii]
AID - JPET_AR2020000370 [pii]
AID - 10.1124/jpet.120.000370 [doi]
PST - ppublish
SO  - J Pharmacol Exp Ther. 2021 Oct;379(1):41-52. doi: 10.1124/jpet.120.000370. Epub 
      2021 Sep 7.