2,6-Disubstituted pyrazines and related analogs as NR2B site antagonists of the NMDA receptor with anti-depressant activity

Brown, Dean G.; Maier, Donna L.; Sylvester, Mark; Hoerter, Tiffany N.; Menhaji‐Klotz, Elnaz; Lasota, Celina C.; Hirata, Lee T.; Wilkins, Deidre; Scott, Clay W.; Trivedi, Shephali; Chen, Tongming; McCarthy, Dennis J.; Maciag, Carla; Sutton, Evelynjeane J.; Cumberledge, Jerry; Mathisen, Don; Roberts, John G.; Gupta, Anshul; Liu, Frank; Elmore, Charles S.; Alhambra, Cristóbal; Krumrine, Jennifer R.; Wang, Xia; Ciaccio, Paul J.; Wood, Michael W.; Campbell, James B.; Johansson, Magnus J.; Xia, Jian X. Richard; Wen, Xiaotian; Jiang, Ji; Wang, Xiaoping; Peng, Zuozhong; Hu, Tao; Wang, Jian

doi:10.1016/j.bmcl.2011.03.117

Cited by 24 publications

(15 citation statements)

References 13 publications

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“…This is in line with multiple prior studies in rats and mice reporting FST antidepressant-like effects of Ro 25-6981 [7, 9, 13, 19–23] or the non-selective NMDAR antagonist, ketamine [2–6, 8–13, 23, 27]. It also resembles the acute FST antidepressant-like phenotype produced by conditional gene deletion of GluN2B on pyramidal neurons throughout the cortex and hippocampus [13], but not by more restricted cortical, plus dorsal CA1 hippocampal, deletion, which only affects FST antidepressant-like behavior after repeated FST [20].…”

Section: Discussionsupporting

confidence: 91%

“…Constitutive deletion of GluN2A in mice mimics the antidepressant-like profile of NMDAR antagonists [18]. Furthermore, systemic administration of compounds that selectively block GluN2B, such as CP-101-606, ifenprodil and Ro 25-6981, produces antidepressant-like effects in rodents [7, 9, 13, 19–23] and therapeutic efficacy in human depression [24]. In mice, deletion of GluN2B in corticohippocampal pyramidal neurons produce an antidepressant-like phenotype when the deletion extends to the ventral hippocampus [13] but only after repeated stress when deletion is restricted to the dorsal CA1 hippocampal subregion [20].…”

Section: Introductionmentioning

confidence: 99%

“…The goal of the current study was to build upon these prior findings to explore how loss of GluA1, GluN1, GluN2A, GluN2B, or PSD-95 affects antidepressant-related behavior, and the antidepressant-related effects of an NMDAR antagonist - using a combination of mutant, pharmacological and virus-based approaches. We focused on a selective GluN2B antagonist (Ro 25-6981), given the aforementioned evidence that this class of drugs has antidepressant-like effects in rodents [7, 9, 19–23] and humans [24]. Antidepressant-related activity was assayed in mice using the FST, a simple behavioral assay sensitive to antidepressant drug treatment [32, 33].…”

Section: Introductionmentioning

confidence: 99%

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NMDA receptor subunits and associated signaling molecules mediating antidepressant-related effects of NMDA-GluN2B antagonism

Kiselycznyk

Jury

Halladay

et al. 2015

Behavioural Brain Research

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Drugs targeting the glutamate N-methyl-D-aspartate receptor (NMDAR) may be efficacious for treating mood disorders, as exemplified by the rapid antidepressant effects produced by single administration of the NMDAR antagonist ketamine. Though the precise mechanisms underlying the antidepressant-related effects of NMDAR antagonism remain unclear, recent studies implicate specific NMDAR subunits, including GluN2A and GluN2B, as well as the alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptor (AMPAR) subunit glutamate receptor interacting molecule, PSD-95. Here, integrating mutant and pharmacological in mice, we investigated the contribution of these subunits and molecules to antidepressant-related behaviors and the antidepressant-related effects of the GluN2B blocker, Ro 25-6981. We found that global deletion of GluA1 or PSD-95 reduced forced swim test (FST) immobility, mimicking the antidepressant-related effect produced by systemically administered Ro 25-6981 in C57BL/6J mice. Moreover, the FST antidepressant-like effects of systemic Ro 25-6981 were intact in mutants with global GluA1 deletion or GluN1 deletion in forebrain interneurons, but were absent in mutants constitutively lacking GluN2A or PSD-95. Next, we found that microinfusing Ro 25-6981 into the medial prefrontal cortex (mPFC), but not basolateral amygdala, of C57BL/6J mice was sufficient to produce an antidepressant-like effect. Together, these findings extend and refine current understanding of the mechanisms mediating antidepressant-like effects produced by NMDAR-GluN2B antagonists, and may inform the development of a novel class of medications for treating depression that target the GluN2B subtype of NMDAR.

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Section: Discussionsupporting

confidence: 91%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

NMDA receptor subunits and associated signaling molecules mediating antidepressant-related effects of NMDA-GluN2B antagonism

Kiselycznyk

Jury

Halladay

et al. 2015

Behavioural Brain Research

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“…Overactivated NMDA receptors are permeable to Na + , K + , and Ca 2+ ions, among which excess Ca 2+ ions is linearly correlated with neuronal cell death triggered by intracellular Ca 2+ -dependent cascades. Many researchers have focused on the extensive studies of GluN2B antagonists because of the ability to potentially cure various CNS diseases (Brown et al, 2011;Cho et al, 2010).…”

Section: Introductionmentioning

confidence: 99%

The neuroprotective effect of praeruptorin C against NMDA-induced apoptosis through down-regulating of GluN2B-containing NMDA receptors

Yang

et al. 2013

Toxicology in Vitro

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“…Due to its role, the over‐stimulation of NMDA receptor has been implicated in several pathological conditions, involving neuronal death and degeneration (e.g., thrombo‐embolic stroke, traumatic head injury, Parkinson’s, Huntington’s, and Alzheimer’s diseases). Therefore, this pathological role has driven the search for NMDA receptor antagonists as a promising therapy (5–8). Currently, the use of NMDA receptor antagonists for acute and chronic neuronal diseases therapy still present undesirable side‐effects, such as motor deficit and sedation that limit their use (9–11).…”

mentioning

confidence: 99%

Molecular Modeling of a Phenyl‐Amidine Class of NMDA Receptor Antagonists and the Rational Design of New Triazolyl‐Amidine Derivatives

et al. 2012

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Recently, many efforts have been made to develop N-methyl-D-aspartic acid receptor antagonists for treating different pathological conditions such as thrombo-embolic stroke, traumatic head injury, Huntington's, Parkinson's, and Alzheimer's diseases). However, as side-effects limit the use of most antagonists, new drugs are still required. In this work, we performed a (quantitative) structure-activity relationship analysis of 17 phenyl-amidine derivatives (1a-1q), reported as N-methyl-D-aspartic acid receptor antagonists, and used this data to rationally design the triazolyl-amidines. The best (quantitative) structure-activity relationship model constructed by multiple linear regression analysis presented high data fitting (R = 0.914) was able to explain 83.6% of the biological data variance (R(2) = 0.836), presented a satisfactory internal predictive ability (Q(2) = 0.609) and contained the descriptors (E(HOMO), Ovality and cLogP). Our assays confirmed that glutamate promotes an extensive cell death in avian neurons (77%) and 2a and 2b protected the neurons from the glutamate effect (from 77% to 27% and 45%, respectively). The results of neurotoxicity and cytotoxicity on Vero cells suggested the favorable profile of 2a and 2b. Also, the molecular modeling used to predict the activity, the interaction with the receptor and the pharmacokinetic and toxicity of the triazolyl-amidines pointed them as a promising class for further exploration as N-methyl-D-aspartic acid receptor antagonists.

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2,6-Disubstituted pyrazines and related analogs as NR2B site antagonists of the NMDA receptor with anti-depressant activity

Cited by 24 publications

References 13 publications

NMDA receptor subunits and associated signaling molecules mediating antidepressant-related effects of NMDA-GluN2B antagonism

NMDA receptor subunits and associated signaling molecules mediating antidepressant-related effects of NMDA-GluN2B antagonism

The neuroprotective effect of praeruptorin C against NMDA-induced apoptosis through down-regulating of GluN2B-containing NMDA receptors

Molecular Modeling of a Phenyl‐Amidine Class of NMDA Receptor Antagonists and the Rational Design of New Triazolyl‐Amidine Derivatives

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