Advancements in NMDA Receptor-Targeted Antidepressants: From d-Cycloserine Discovery to Preclinical Efficacy of Lu AF90103.

The discovery of d-cycloserine (), a partial agonist of the NMDA receptor that exhibits antidepressant effects without the psychotomimetic effects of ketamine, has fueled interest in new NMDA-targeting antidepressants. Our objective was to identify potent partial agonists mirroring , particularly tailored for the GluN2B subtype of the NMDA receptor. Through a structure-based drug design approach, we discovered compound .

Synthesis and Characterization of the Novel Rodent-Active and CNS-Penetrant P2X7 Receptor Antagonist Lu AF27139.

There remains an insufficient number of P2X7 receptor antagonists with adequate rodent potency, CNS permeability, and pharmacokinetic properties from which to evaluate CNS disease hypotheses preclinically. Herein, we describe the molecular pharmacology, safety, pharmacokinetics, and functional CNS target engagement of Lu AF27139, a novel rodent-active and CNS-penetrant P2X7 receptor antagonist. Lu AF27139 is highly selective and potent against rat, mouse, and human forms of the receptors.

BN/CC isosterism in borazaronaphthalenes towards phosphodiesterase 10A (PDE10A) inhibitors.

The application of BN/CC isosterism is explored as a method of expanding the scope of core scaffolds in biologically active compounds. The viability of potential drug candidates incorporating BN-heteroaromatic moieties was investigated through the synthesis of BN-substituted analogs to known phosphodiesterase (PDE10A) inhibitors, namely MP10 and a selection of N-methylanilide analogs. These in some cases revealed unexpectedly potent and relatively stable derivatives, providing further support for the potential of BN-incorporation in medicinal chemistry.

Discovery and development of 11C-Lu AE92686 as a radioligand for PET imaging of phosphodiesterase10A in the brain.

Unlabelled: Phosphodiesterase 10A (PDE10A) plays a key role in the regulation of brain striatal signaling, and several pharmaceutical companies currently investigate PDE10A inhibitors in clinical trials for various central nervous system diseases. A PDE10A PET ligand may provide evidence that a clinical drug candidate reaches and binds to the target. Here we describe the successful discovery and initial validation of the novel radiolabeled PDE10A ligand 5,8-dimethyl-2-[2-((1-(11)C-methyl)-4-phenyl-1H-imidazol-2-yl)-ethyl]-[1,2,4]triazolo[1,5-a]pyridine ((11)C-Lu AE92686) and its tritiated analog (3)H-Lu AE92686.

N-Methylanilide and N-methylbenzamide derivatives as phosphodiesterase 10A (PDE10A) inhibitors.

PDE10A is a recently identified phosphodiesterase with a quite remarkable localization since the protein is abundant only in brain tissue. Based on this unique localization, research has focused extensively on using PDE10A modulators as a novel therapeutic approach for dysfunction in the basal ganglia circuit including Parkinson's disease, Huntington's disease, schizophrenia, addiction and obsessive compulsive disorder. Medicinal chemistry efforts identified the N-methyl-N-[4-(quinolin-2-ylmethoxy)-phenyl]-isonicotinamide (8) as a nanomolar PDE10A inhibitor.

Do cell phones, iPods/MP3 players, siblings and friends matter? Predictors of child body mass in a U.S. Southern Border City Middle School.

Objective: This study examines the association of children's (i) micro-social environment, specifically siblings [kin-friends] and friends from school and neighborhood [non-kin-friends], and (ii) ownership of information and communication technologies (ICT), specifically cell phones and iPod/MP3 players, with body mass index percentile (BMIp).

Subjects: Fifty-five randomly selected 6th graders with a mean age of 12 years, stratified by gender (23 boys and 32 girls), from a Texas middle school located in a city along the U.S.

Triazoloquinazolines as a novel class of phosphodiesterase 10A (PDE10A) inhibitors.

Novel triazoloquinazolines have been found as phosphodiesterase 10A (PDE10A) inhibitors. Structure-activity studies improved the initial micromolar potency which was found in the lead compound by a 100-fold identifying 5-(1H-benzoimidazol-2-ylmethylsulfanyl)-2-methyl-[1,2,4]triazolo[1,5-c]quinazoline, 42 (PDE10A IC(50)=12 nM) as the most potent compound from the series. Two X-ray structures revealed novel binding modes to the catalytic site of the PDE10A enzyme.

Much ado about nothing: the misestimation and overinterpretation of violent video game effects in eastern and western nations: comment on Anderson et al. (2010).

The issue of violent video game influences on youth violence and aggression remains intensely debated in the scholarly literature and among the general public. Several recent meta-analyses, examining outcome measures most closely related to serious aggressive acts, found little evidence for a relationship between violent video games and aggression or violence. In a new meta-analysis, C.

Patented PDE10A inhibitors: novel compounds since 2007.

Importance Of The Field: PDE10A inhibition has generated much excitement as a potential novel mechanism for the treatment of the positive symptoms of schizophrenia. PDE10A is only '10 years old' as a drug discovery target since it was first discovered in 1999, and thus PDE10A is an example of the modern drug discovery paradigm demonstrating the highly increased speed by which novel targets can be validated, hits identified, lead-optimization performed and compounds progressed into clinical trials. At least one PDE10A inhibitor compound has been progressed to clinical Phase II for the treatment of schizophrenia.

The public health risks of media violence: a meta-analytic review.

Objective: To conduct a meta-analytic review of studies that examine the impact of violent media on aggressive behavior and to determine whether this effect could be explained through methodological problems inherent in this research field.

Study Design: A detailed literature search identified peer-reviewed articles addressing media violence effects. Effect sizes were calculated for all studies.

Highly functionalized organolithium reagents for enantiomerically pure alpha-amino acid synthesis.

[reaction: see text] Highly functionalized l-serine-derived organolithium reagents have been generated and reacted with a variety of electrophiles, delivering novel enantiomerically pure adducts. These adducts were then converted into homochiral amino alcohols and novel nonproteinogenic alpha-amino acids, including an aspartic acid mimic that has been synthesized in an enantiomerically pure form for the first time.