Metabolism studies of ifenprodil, a potent GluN2B receptor antagonist

Falck, Evamaria; Begrow, Frank; Verspohl, Eugen J.; Wünsch, Bernhard

doi:10.1016/j.jpba.2013.08.014

Cited by 44 publications

(28 citation statements)

References 13 publications

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“…The concentration of ifenprodil used in the present study (4.16 mM) was higher than the IC50 for GluN2A containing NMDA receptors. There are mitigating factors to consider, such as the fact that the IC50s for ifenprodil were measured in Xenopus oocytes in vitro , or how far ifenprodil spread from the point of infusion thereby diluting it [102], as well as metabolic breakdown of ifenprodil in vivo after infusion took place [103] which would effectively lower the concentration of ifenprodil at neuronal synapses in AIC. While we met our goal of evaluating the differential effects of ifenprodil on behaviors and communication between control and PAE animals, the only way to be completely sure that the effects of ifenprodil were caused by inhibiting GluN2B-containing NMDA receptors will be to infuse a dose that is lower than the IC50 for GluN2A-containing NMDA receptors.…”

Section: Discussionmentioning

confidence: 99%

Ifenprodil infusion in agranular insular cortex alters social behavior and vocalizations in rats exposed to moderate levels of ethanol during prenatal development

Bird

Barto

Magcalas

et al. 2017

Behavioural Brain Research

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Moderate exposure to alcohol during development leads to subtle neurobiological and behavioral effects classified under the umbrella term fetal alcohol spectrum disorders (FASDs). Alterations in social behaviors are a frequently observed consequence of maternal drinking, as children with FASDs display inappropriate aggressive behaviors and altered responses to social cues. Rodent models of FASDs mimic the behavioral alterations seen in humans, with rats exposed to ethanol during development displaying increased aggressive behaviors, decreased social investigation, and altered play behavior. Work from our laboratory has observed increased wrestling behavior in adult male rats following prenatal alcohol exposure (PAE), and increased expression of GluN2B-containing NMDA receptors in the agranular insular cortex (AIC). This study was undertaken to determine if ifenprodil, a GluN2B preferring negative allosteric modulator, has a significant effect on social behaviors in PAE rats. Using a voluntary ethanol exposure paradigm, rat dams were allowed to drink a saccharin-sweetened solution of either 0% or 5% ethanol throughout gestation. Offspring at 6–8 months of age were implanted with cannulae into AIC. Animals were isolated for 24 hours before ifenprodil or vehicle was infused into AIC, and after 15 minutes they were recorded in a social interaction chamber. Ifenprodil treatment altered aspects of wrestling, social investigatory behaviors, and ultrasonic vocalizations in rats exposed to ethanol during development that were not observed in control animals. These data indicate that GluN2B-containing NMDA receptors in AIC play a role in social behaviors and may underlie alterations in behavior and vocalizations observed in PAE animals.

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Section: Discussionmentioning

confidence: 99%

Ifenprodil infusion in agranular insular cortex alters social behavior and vocalizations in rats exposed to moderate levels of ethanol during prenatal development

Bird

Barto

Magcalas

et al. 2017

Behavioural Brain Research

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“…However,d ue to its low selectivity and bioavailability,t he clinical development of compound 1 was discontinued. [13] In 2011adimer of the ATDs of the GluN1ba nd GluN2B subunits wasc o-crystallized with 1 and Ro-25-6981 (2). [14] Unexpectedly, the binding site of the GluN2B-selective ligandsw as found at the interface between the GluN1b and GluN2B subunits instead solely within the GluN2B subunit.…”

Section: Introductionmentioning

confidence: 99%

Design, Synthesis, Pharmacological Evaluation and Docking Studies of GluN2B‐Selective NMDA Receptor Antagonists with a Benzo[7]annulen‐7‐amine Scaffold

et al. 2017

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Antagonists that selectively target GluN2B-subunit-containing N-methyl-d-aspartate (NMDA) receptors are of major interest for the treatment of various neurological disorders. In this study, relationships between variously substituted benzo[7]annulen-7-amines and their GluN2B affinity were investigated. 2-Nitro-5,6,8,9-tetrahydrobenzo[7]annulen-7-one (8) represents the central building block for the introduction of various substituents at the 2-position and various 7-amino moieties. N-(3-Phenylpropyl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-7-amines with a 2-NO (7 c), 2-Cl (15 c), or 2-OBn group (22 c) show very high GluN2B affinity (K =1.6-3.6 nm). Docking studies revealed the same binding poses for benzo[7]annulen-7-amines and ifenprodil at the interface of GluN1b and GluN2B subunits. The large 2-OBn moiety of 22 c occupies a previously unrecognized subpocket, which explains its high GluN2B affinity (K =3.6 nm). In two-electrode voltage clamp experiments and cytoprotection assays, the high-affinity GluN2B ligands 7 c, 15 c, and 22 c could not inhibit the glutamate-/glycine-evoked current and cytotoxic effects. However, the analogous phenols 16 c ((3-phenylpropyl)amino moiety) and 16 d ((4-phenylbutyl)amino moiety) with 10-fold lower GluN2B affinity (K =28 and 21 nm, respectively) showed promising inhibition of glutamate-/glycine-evoked effects in both assays. The presence of a phenolic hydroxy group seems to be essential for inducing conformational changes of the receptor protein, which finally results in closure of the ion conduction pathway.

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“…14 However, the clinical development of 1 was terminated due to undesired side effects and low bioavailability. 15 Additionally, lack of selectivity of ifenprodil interacting with 5-HT 1A , 5-HT 2 , α 1 , σ 1 , and σ 2 receptors was observed.…”

Section: Introductionmentioning

confidence: 98%