Excellence in Medicinal Chemistry: Celebrating ACS Medicinal Chemistry Division (MEDI) Awards. A Call for Nominations.

The American Chemical Society Division of Medicinal Chemistry (MEDI) confers a range of awards, fellowships and honors to recognize excellence in medicinal chemistry. To celebrate the creation of the Gertrude Elion Medical Chemistry Award the ACS MEDI Division wishes to take this opportunity to inform the community of the many awards, fellowships and travel grants that are available for members.

Mark I. Appelbaum (1941-2020).

Memorializes Mark I. Appelbaum (1941-2020). Appelbaum was a giant in the field of quantitative psychology and developmental methodology.

Novel Trifluoromethyl Pyrimidinone Compounds With Activity Against .

The identification and development of new anti-tubercular agents are a priority research area. We identified the trifluoromethyl pyrimidinone series of compounds in a whole-cell screen against . Fifteen primary hits had minimum inhibitory concentrations (MICs) with good potency IC is the concentration at which growth is inhibited by 90% (IC < 5 μM).

Modulation of TARP 8-Containing AMPA Receptors as a Novel Therapeutic Approach for Chronic Pain.

Nonselective glutamate -amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor antagonists are efficacious in chronic pain but have significant tolerability issues, likely arising from the ubiquitous expression of AMPA receptors in the central nervous system (CNS). Recently, LY3130481 has been shown to selectively block AMPA receptors coassembled with the auxiliary protein, transmembrane AMPA receptor regulatory protein (TARP) 8, which is highly expressed in the hippocampus but also in pain pathways, including anterior cingulate (ACC) and somatosensory cortices and the spinal cord, suggesting that selective blockade of 8/AMPA receptors may suppress nociceptive signaling with fewer CNS side effects. The potency of LY3130481 on recombinant 8-containing AMPA receptors was modulated by coexpression with other TARPs; 2 subunits affected activity more than 3 subunits.

Developmental trajectories of executive functions in young males with fragile X syndrome.

Background: Executive functions (EF) have been identified as impaired in FXS, but few studies have examined their developmental trajectories.

Aims: The primary aim of this longitudinal study was to examine the development of EF in young males with FXS compared to Mental Age (MA)-matched controls.

Methods And Procedures: The sample comprised 56 boys with FXS (ages 7-13 years), and 48 MA-matched typical boys (ages 4-8 years).

Determinants of memory development in childhood and adolescence.

Research on the development of memory has a long history and constitutes one of the most active research areas in the field of cognitive development. In this article, we first describe major historical developments in the literature on children's memory, focusing on systematic research that began in the late 1960s. We then examine new developments in the field, describing four important lines of inquiry: (a) the development of implicit memory, (b) short- and long-term memory development in infancy, (c) longitudinal research on memory strategies and metamemory, and (d) developmental cognitive neuroscience of memory.

The Socialization of Children's Memory: Linking Maternal Conversational Style to the Development of Children's Autobiographical and Deliberate Memory Skills.

Data from a large-scale, longitudinal research study with an ethnically and socioeconomically diverse sample were utilized to explore linkages between maternal elaborative conversational style and the development of children's autobiographical and deliberate memory. Assessments were made when the children were 3, 5, and 6 years of age, and the results reveal concurrent and longitudinal linkages between maternal conversational style in a mother-child reminiscing task and children's autobiographical memory performance. Maternal conversational style while reminiscing was also significantly related to children's strategic behaviors and recall in two deliberate memory tasks, both concurrently and longitudinally.

The synthesis and evaluation of triazolopyrimidines as anti-tubercular agents.

We identified a di-substituted triazolopyrimidine with anti-tubercular activity against Mycobacterium tuberculosis. Three segments of the scaffold were examined rationally to establish a structure-activity relationship with the goal of improving potency and maintaining good physicochemical properties. A number of compounds displayed sub-micromolar activity against Mycobacterium tuberculosis with no cytotoxicity against eukaryotic cells.

Diabetes Resolution and Work Absenteeism After Gastric Bypass: a 6-Year Study.

Background: Obesity-related diseases cause costs to society. We studied the cost of work absenteeism before and after gastric bypass and the effects of postoperative diabetes resolution.

Patients And Methods: Data were obtained from the Scandinavian Obesity Surgery Registry (SOReg) (national coverage >98%) and cross-matched with data from the Social insurance Agency (coverage 100%) for the period ±3 years from operation.

Preclinical predictors that the orthosteric mGlu2/3 receptor antagonist LY3020371 will not engender ketamine-associated neurotoxic, motor, cognitive, subjective, or abuse-liability-related effects.

The novel mGlu2/3 receptor antagonist, LY3020371, has been shown to produce antidepressant-like effects comparable to that of the clinically-effective antidepressant ketamine. In the present study, we investigated whether LY3020371 would be predicted to be free of the side-effects and safety pharmacology issues associated with ketamine. In contrast to ketamine, LY3020371 produced small increases in locomotion and did not impair motor performance on an inverted screen.

Comparative Effects of LY3020371, a Potent and Selective Metabotropic Glutamate (mGlu) 2/3 Receptor Antagonist, and Ketamine, a Noncompetitive -Methyl-d-Aspartate Receptor Antagonist in Rodents: Evidence Supporting the Use of mGlu2/3 Antagonists, for the Treatment of Depression.

The ability of the -methyl-d-aspartate receptor antagonist ketamine to alleviate symptoms in patients suffering from treatment-resistant depression (TRD) is well documented. In this paper, we directly compare in vivo biologic responses in rodents elicited by a recently discovered metabotropic glutamate (mGlu) 2/3 receptor antagonist 2-amino-3-[(3,4-difluorophenyl)sulfanylmethyl]-4-hydroxy-bicyclo[3.1.

Discovery of (1S,2R,3S,4S,5R,6R)-2-Amino-3-[(3,4-difluorophenyl)sulfanylmethyl]-4-hydroxy-bicyclo[3.1.0]hexane-2,6-dicarboxylic Acid Hydrochloride (LY3020371·HCl): A Potent, Metabotropic Glutamate 2/3 Receptor Antagonist with Antidepressant-Like Activity.

As part of our ongoing efforts to identify novel ligands for the metabotropic glutamate 2 and 3 (mGlu) receptors, we have incorporated substitution at the C3 and C4 positions of the (1S,2R,5R,6R)-2-amino-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid scaffold to generate mGlu antagonists.

Novel bicyclo[3.1.0]hexane analogs as antagonists of metabotropic glutamate 2/3 receptors for the treatment of depression.

Negative modulators of metabotropic glutamate 2 & 3 receptors demonstrate antidepressant-like activity in animal models and hold promise as novel therapeutic agents for the treatment of major depressive disorder. Herein we describe our efforts to prepare and optimize a series of conformationally constrained 3,4-disubstituted bicyclo[3.1.

Forebrain-selective AMPA-receptor antagonism guided by TARP γ-8 as an antiepileptic mechanism.

Pharmacological manipulation of specific neural circuits to optimize therapeutic index is an unrealized goal in neurology and psychiatry. AMPA receptors are important for excitatory synaptic transmission, and their antagonists are antiepileptic. Although efficacious, AMPA-receptor antagonists, including perampanel (Fycompa), the only approved antagonist for epilepsy, induce dizziness and motor impairment.

Discovery of the First α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid (AMPA) Receptor Antagonist Dependent upon Transmembrane AMPA Receptor Regulatory Protein (TARP) γ-8.

Transmembrane AMPA receptor regulatory proteins (TARPs) are a family of scaffolding proteins that regulate AMPA receptor trafficking and function. TARP γ-8 is one member of this family and is highly expressed within the hippocampus relative to the cerebellum. A selective TARP γ-8-dependent AMPA receptor antagonist (TDAA) is an innovative approach to modulate AMPA receptors in specific brain regions to potentially increase the therapeutic index relative to known non-TARP-dependent AMPA antagonists.

In vitro pharmacological and rat pharmacokinetic characterization of LY3020371, a potent and selective mGlu receptor antagonist.

Metabotropic glutamate (mGlu) receptors are of considerable interest owing to their role in modulating glutamate transmission via presynaptic, postsynaptic and glial mechanisms. As part of our ongoing efforts to identify novel ligands for these receptors, we have discovered (1S,2R,3S,4S,5R,6R)-2-amino-3-[(3,4-difluorophenyl)sulfanylmethyl]-4-hydroxy-bicyclo[3.1.

Asymptotic Properties of Spearman's Rank Correlation for Variables with Finite Support.

The asymptotic variance and distribution of Spearman's rank correlation have previously been known only under independence. For variables with finite support, the population version of Spearman's rank correlation has been derived. Using this result, we show convergence to a normal distribution irrespectively of dependence, and derive the asymptotic variance.

Change over Time: Conducting Longitudinal Studies of Children's Cognitive Development.

Developmental scientists have argued that the implementation of longitudinal methods is necessary for obtaining an accurate picture of the nature and sources of developmental change (Magnusson & Cairns, 1996; Morrison & Ornstein, 1996; Magnusson & Stattin, 2006). Developmentalists studying cognition have been relatively slow to embrace longitudinal research, and thus few exemplar studies have tracked individual children's cognitive performance over time and even fewer have examined contexts that are associated with this growth. In this article we first outline some of the benefits of implementing longitudinal designs.

Intimate partner violence and children's memory.

The current study was designed to examine the relation between intimate partner violence (IPV) and children's memory and drew from a socioeconomically and racially diverse sample of children living in and around a midsized southeastern city (n = 140). Mother-reported IPV when the children were 30 months old was a significant predictor of children's short-term, working, and deliberate memory at 60 months of age, even after controlling for the children's sex and race, the families' income-to-needs ratio, the children's expressive vocabulary, and maternal harsh-intrusive parenting behaviors. These findings add to the limited extant literature that finds linkages between IPV and children's cognitive functioning and suggest that living in households in which physical violence is perpetrated among intimate partners may have a negative effect on multiple domains of children's memory development.

GluK1 antagonists from 6-(tetrazolyl)phenyl decahydroisoquinoline derivatives: in vitro profile and in vivo analgesic efficacy.

We have explored the decahydroisoquinoline scaffold, bearing a phenyl tetrazole, as GluK1 antagonists with potential as oral analgesics. We have established the optimal linker atom between decahydroisoquinoline and phenyl rings and demonstrated an improvement of both the affinity for the GluK1 receptor and the selectivity against the related GluA2 receptor with proper phenyl substitution. In this Letter, we also disclose in vivo data that led to the discovery of LY545694·HCl, a compound with oral efficacy in two persistent pain models.

GluK1 antagonists from 6-(carboxy)phenyl decahydroisoquinoline derivatives. SAR and evaluation of a prodrug strategy for oral efficacy in pain models.

The synthesis and structure-activity relationship of decahydroisoquinoline derivatives with various benzoic acid substitutions as GluK1 antagonists are described. Potent and selective antagonists were selected for a tailored prodrug approach in order to facilitate the evaluation of the new compounds in pain models after oral administration. Several diester prodrugs allowed for acceptable amino acid exposure and moderate efficacy in vivo.

When does intimate partner violence continue after separation?

Over their lifetime, approximately 10% of all women become victims of postseparation stalking or assault. We use a nationally representative survey of separated Swedish women to examine whether men who strive to control their partners during their relationships are more likely to stalk or assault their ex-partners after separation. The empirical analysis shows that basic measures of control behaviors explain 18% of the variance in stalking victimization and 8% of the assault victimization.

The effect of teachers' memory-relevant language on children's strategy use and knowledge.

Building on longitudinal findings of linkages between aspects of teachers' language during instruction and children's use of mnemonic strategies, this investigation was designed to examine experimentally the impact of instruction on memory development. First and second graders (N = 54, M(age) = 7 years) were randomly assigned to a science unit that varied only in teachers' use of memory-relevant language. Pretest, posttest, and 1-month follow-up assessments revealed that although all participating children learned new information as a result of instruction, those exposed to memory rich teaching exhibited greater levels of strategic knowledge and engaged in more sophisticated strategy use in a memory task involving instructional content than did students exposed to low memory instruction.

Coherence of Personal Narratives across the Lifespan: A Multidimensional Model and Coding Method.

Personal narratives are integral to autobiographical memory and to identity, with coherent personal narratives being linked to positive developmental outcomes across the lifespan. In this article, we review the theoretical and empirical literature that sets the stage for a new lifespan model of personal narrative coherence. This new model integrates context, chronology, and theme as essential dimensions of personal narrative coherence, each of which relies upon different developmental achievements and has a different developmental trajectory across the lifespan.