Santangelo Freel RM et al. (2013), Synthesis and structure activity relationship o...

XB-ART-46964

J Med Chem 2013 Jul 11;5613:5351-81. doi: 10.1021/jm400177t.

Show Gene links Show Anatomy links

Synthesis and structure activity relationship of tetrahydroisoquinoline-based potentiators of GluN2C and GluN2D containing N-methyl-D-aspartate receptors.

Santangelo Freel RM , Ogden KK , Strong KL , Khatri A , Chepiga KM , Jensen HS , Traynelis SF , Liotta DC .

???displayArticle.abstract???
We describe here the synthesis and evaluation of a series of tetrahydroisoquinolines that show subunit-selective potentiation of NMDA receptors containing the GluN2C or GluN2D subunits. Bischler-Napieralski conditions were employed in the key step for the conversion of acyclic amides to the corresponding tetrahydroisoquinoline-containing analogs. Compounds were evaluated using both two-electrode voltage clamp recordings from Xenopus laevis oocytes and imaging of mammalian BHK cells loaded with Ca(2+)-sensitive dyes. The most potent analogues had EC50 values of 300 nM and showed over 2-fold potentiation of the response to maximally effective concentrations of glutamate and glycine but had no effect on responses from NMDA receptors containing the GluN2A or GluN2B subunits AMPA, kainate, and GABA or glycine receptors or a variety of other potential targets. These compounds represent a potent class of small molecule subunit-selective potentiators of NMDA receptors.

???displayArticle.pubmedLink??? 23627311
???displayArticle.pmcLink??? PMC4850841
???displayArticle.link??? J Med Chem
???displayArticle.grants??? [+]

References [+] :

aan het Rot, Safety and efficacy of repeated-dose intravenous ketamine for treatment-resistant depression. 2010, Pubmed

aan het Rot, Safety and efficacy of repeated-dose intravenous ketamine for treatment-resistant depression. 2010, Pubmed
Acker, Mechanism for noncompetitive inhibition by novel GluN2C/D N-methyl-D-aspartate receptor subunit-selective modulators. 2011, Pubmed
Akazawa, Differential expression of five N-methyl-D-aspartate receptor subunit mRNAs in the cerebellum of developing and adult rats. 1994, Pubmed
Anson, Identification of amino acid residues of the NR2A subunit that control glutamate potency in recombinant NR1/NR2A NMDA receptors. 1998, Pubmed
Antonov, Binding sites for permeant ions in the channel of NMDA receptors and their effects on channel block. 1998, Pubmed
Banke, Activation of NR1/NR2B NMDA receptors. 2003, Pubmed
Bettini, Identification and characterization of novel NMDA receptor antagonists selective for NR2A- over NR2B-containing receptors. 2010, Pubmed
Chen, Modulation of glycine potency in rat recombinant NMDA receptors containing chimeric NR2A/2D subunits expressed in Xenopus laevis oocytes. 2008, Pubmed , Xenbase
Citri, Synaptic plasticity: multiple forms, functions, and mechanisms. 2008, Pubmed
Costa, Structure-activity relationships for allosteric NMDA receptor inhibitors based on 2-naphthoic acid. 2012, Pubmed , Xenbase
Costa, A novel family of negative and positive allosteric modulators of NMDA receptors. 2010, Pubmed , Xenbase
Coyle, NMDA receptor and schizophrenia: a brief history. 2012, Pubmed
Cull-Candy, Role of distinct NMDA receptor subtypes at central synapses. 2004, Pubmed
Dravid, Activation of recombinant NR1/NR2C NMDA receptors. 2008, Pubmed
Dravid, Structural determinants of D-cycloserine efficacy at the NR1/NR2C NMDA receptors. 2010, Pubmed , Xenbase
Durand, Splice variants of the N-methyl-D-aspartate receptor NR1 identify domains involved in regulation by polyamines and protein kinase C. 1993, Pubmed , Xenbase
Endele, Mutations in GRIN2A and GRIN2B encoding regulatory subunits of NMDA receptors cause variable neurodevelopmental phenotypes. 2010, Pubmed
Erreger, Subunit-specific agonist activity at NR2A-, NR2B-, NR2C-, and NR2D-containing N-methyl-D-aspartate glutamate receptors. 2007, Pubmed , Xenbase
Faden, The role of excitatory amino acids and NMDA receptors in traumatic brain injury. 1989, Pubmed
Furukawa, Mechanisms of activation, inhibition and specificity: crystal structures of the NMDA receptor NR1 ligand-binding core. 2003, Pubmed
Hallett, Rationale for and use of NMDA receptor antagonists in Parkinson's disease. 2004, Pubmed
Hansen, Structural and mechanistic determinants of a novel site for noncompetitive inhibition of GluN2D-containing NMDA receptors. 2011, Pubmed , Xenbase
Hansen, Subunit-selective allosteric inhibition of glycine binding to NMDA receptors. 2012, Pubmed
Hansen, Implementation of a fluorescence-based screening assay identifies histamine H3 receptor antagonists clobenpropit and iodophenpropit as subunit-selective N-methyl-D-aspartate receptor antagonists. 2010, Pubmed , Xenbase
Heresco-Levy, N-Methyl-D-aspartate (NMDA) receptor-based treatment approaches in schizophrenia: the first decade. 2000, Pubmed
Hillman, Behavioral analysis of NR2C knockout mouse reveals deficit in acquisition of conditioned fear and working memory. 2011, Pubmed
Irvine, Coumarin-3-carboxylic acid derivatives as potentiators and inhibitors of recombinant and native N-methyl-D-aspartate receptors. 2012, Pubmed
Jones, Functional NR2B- and NR2D-containing NMDA receptor channels in rat substantia nigra dopaminergic neurones. 2005, Pubmed
Karakas, Subunit arrangement and phenylethanolamine binding in GluN1/GluN2B NMDA receptors. 2011, Pubmed , Xenbase
Kashiwagi, Channel blockers acting at N-methyl-D-aspartate receptors: differential effects of mutations in the vestibule and ion channel pore. 2002, Pubmed , Xenbase
Kerchner, Silent synapses and the emergence of a postsynaptic mechanism for LTP. 2008, Pubmed
Korotkova, NMDA receptor ablation on parvalbumin-positive interneurons impairs hippocampal synchrony, spatial representations, and working memory. 2010, Pubmed
Kuryatov, Mutational analysis of the glycine-binding site of the NMDA receptor: structural similarity with bacterial amino acid-binding proteins. 1994, Pubmed , Xenbase
Laube, Molecular determinants of agonist discrimination by NMDA receptor subunits: analysis of the glutamate binding site on the NR2B subunit. 1997, Pubmed
Lisman, Circuit-based framework for understanding neurotransmitter and risk gene interactions in schizophrenia. 2008, Pubmed
Masuko, Stimulatory and inhibitory properties of aminoglycoside antibiotics at N-methyl-D-aspartate receptors. 1999, Pubmed , Xenbase
Menniti, Allosteric modulators for the treatment of schizophrenia: targeting glutamatergic networks. 2013, Pubmed
Milnerwood, Early synaptic pathophysiology in neurodegeneration: insights from Huntington's disease. 2010, Pubmed
Moghaddam, From revolution to evolution: the glutamate hypothesis of schizophrenia and its implication for treatment. 2012, Pubmed
Monyer, Developmental and regional expression in the rat brain and functional properties of four NMDA receptors. 1994, Pubmed
Morikawa, Attenuation of focal ischemic brain injury in mice deficient in the epsilon1 (NR2A) subunit of NMDA receptor. 1998, Pubmed
Morris, PCP: from pharmacology to modelling schizophrenia. 2005, Pubmed
Mosley, Quinazolin-4-one derivatives: A novel class of noncompetitive NR2C/D subunit-selective N-methyl-D-aspartate receptor antagonists. 2010, Pubmed , Xenbase
Mullasseril, A subunit-selective potentiator of NR2C- and NR2D-containing NMDA receptors. 2010, Pubmed
Nakazawa, GABAergic interneuron origin of schizophrenia pathophysiology. 2012, Pubmed
Ogden, New advances in NMDA receptor pharmacology. 2011, Pubmed
Ono, 18F-labeled flavones for in vivo imaging of beta-amyloid plaques in Alzheimer's brains. 2009, Pubmed
Park, The glutamate antagonist MK-801 reduces focal ischemic brain damage in the rat. 1988, Pubmed
Preskorn, An innovative design to establish proof of concept of the antidepressant effects of the NR2B subunit selective N-methyl-D-aspartate antagonist, CP-101,606, in patients with treatment-refractory major depressive disorder. 2008, Pubmed
Rebola, Activity-dependent synaptic plasticity of NMDA receptors. 2010, Pubmed
Reisberg, Memantine in moderate-to-severe Alzheimer's disease. 2003, Pubmed
Sakurada, Alteration of Ca2+ permeability and sensitivity to Mg2+ and channel blockers by a single amino acid substitution in the N-methyl-D-aspartate receptor. 1993, Pubmed , Xenbase
Santangelo Freel, Correction to Synthesis and Structure Activity Relationship of Tetrahydroisoquinoline-Based Potentiators of GluN2C and GluN2D Containing N-Methyl-d-aspartate Receptors. 2014, Pubmed
Schwartz, Glutamate neurocircuitry: theoretical underpinnings in schizophrenia. 2012, Pubmed
Sheinin, Subunit specificity and mechanism of action of NMDA partial agonist D-cycloserine. 2001, Pubmed , Xenbase
Simon, Blockade of N-methyl-D-aspartate receptors may protect against ischemic damage in the brain. 1984, Pubmed
Suetake-Koga, In vitro and antinociceptive profile of HON0001, an orally active NMDA receptor NR2B subunit antagonist. 2006, Pubmed
Tolias, The Rac1-GEF Tiam1 couples the NMDA receptor to the activity-dependent development of dendritic arbors and spines. 2005, Pubmed
Traynelis, Control of voltage-independent zinc inhibition of NMDA receptors by the NR1 subunit. 1998, Pubmed , Xenbase
Traynelis, Glutamate receptor ion channels: structure, regulation, and function. 2010, Pubmed
Traynelis, Control of proton sensitivity of the NMDA receptor by RNA splicing and polyamines. 1995, Pubmed , Xenbase
Vicini, Functional and pharmacological differences between recombinant N-methyl-D-aspartate receptors. 1998, Pubmed
Williams, Characterization of polyamines having agonist, antagonist, and inverse agonist effects at the polyamine recognition site of the NMDA receptor. 1990, Pubmed
Wu, Targeting the NMDA receptor subunit NR2B for the treatment of neuropathic pain. 2009, Pubmed
Wu, Pregnenolone sulfate: a positive allosteric modulator at the N-methyl-D-aspartate receptor. 1991, Pubmed
Wyllie, Single-channel activations and concentration jumps: comparison of recombinant NR1a/NR2A and NR1a/NR2D NMDA receptors. 1998, Pubmed , Xenbase
Youte, An enantioselective access to 1-alkyl-1,2,3,4-tetrahydroisoquinolines. Application to a new synthesis of (-)-argemonine. 2004, Pubmed