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Abuse of novel arylcyclohexylamines (ACX) poses risks for toxicities, including adverse neurocognitive effects. In vivo effects of ring-substituted analogs of phencyclidine (PCP), eticyclidine (PCE), and ketamine are understudied. Adult male National Institutes of Health Swiss mice were used to assess locomotor effects of PCP and its 3-OH, 3-MeO, 3-Cl, and 4-MeO analogs, PCE and its 3-OH and 3-MeO analogs, and ketamine and its deschloro and 2F-deschloro analogs, in comparison with those of methamphetamine (METH), 3,4-methylenedioxymethamphetamine (MDMA), and two benzofuran analogs of MDMA. PCP-like interoceptive effects for all of these ACXs were determined using a food-reinforced drug discrimination procedure in adult male Sprague Dawley rats. A novel operant assay of rule-governed behavior incorporating aspects of attentional set-shifting was used to profile psychosis-like neurocognitive effects of PCP and 3-Cl-PCP in rats, in comparison with cocaine and morphine. PCP-like ACXs were more effective locomotor stimulants than the amphetamines, PCE-like ACXs were as effective as the amphetamines, and ketamine-like ACXs were less effective than the amphetamines. Addition of -Cl, -OH, or -OMe at the 3-position on the aromatic ring did not impact locomotor effectiveness, but addition of -OMe at the 4-position reduced locomotor effectiveness. Lethal effects were induced by drugs with -OH at the 3-position or -OMe at the 3- or 4-position. All novel ACXs substituted at least partially for PCP, and PCP and 3-Cl-PCP elicited dose-dependent psychosis-like neurocognitive deficits in the rule-governed behavior task not observed with cocaine or morphine. Novel ACXs exhibit substantial abuse liability and toxicities not necessarily observed with their parent drugs. SIGNIFICANCE STATEMENT: Novel arylcyclohexylamine analogs of PCP, PCE, and ketamine are appearing on the illicit market, and abuse of these drugs poses risks for toxicities, including adverse neurocognitive effects. These studies demonstrate that the novel ACXs exhibit PCP-like abuse liability in the drug discrimination assay, elicit varied locomotor stimulant and lethal effects in mice, and induce psychosis-like neurocognitive effects in rats.

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There is substantial evidence that cholinergic system function impairment plays a significant role in many central nervous system (CNS) disorders. During the past three decades, muscarinic receptors (mAChRs) have been implicated in various pathologies and have been prominent targets of drug-design efforts. However, due to the high sequence homology of the orthosteric binding site, many drug candidates resulted in limited clinical success. Although several advances in treating peripheral pathologies have been achieved, targeting CNS pathologies remains challenging for researchers. Nevertheless, significant progress has been made in recent years to develop functionally selective orthosteric and allosteric ligands targeting the mAChRs with limited side effect profiles. This review highlights past efforts and focuses on recent advances in drug design targeting these receptors for Alzheimer's disease (AD), schizophrenia (SZ), and depression.

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The cholinergic nervous system has been implicated in mood disorders, evident in the fast-onset antidepressant effects of scopolamine, a potent muscarinic antagonist, in clinical studies. One prominent disadvantage of the use of scopolamine in the treatment of depression is its detrimental effects on cognition, especially as such effects might aggravate cognitive deficits that occur with depression itself. Thus, the identification of antimuscarinic drugs that are free of such detrimental effects may provide an important avenue for the development of novel therapeutics for the management of depression. The present data in rats indicate that a historical muscarinic antagonist, L-687,306, and a muscarinic antagonist of our own design, CJ2100, were as or more effective than scopolamine in antagonizing both the bradycardic effects of the muscarinic agonist arecoline in cardiovascular studies and its discriminative stimulus and rate-decreasing effects in behavioral studies. Additionally, both novel muscarinic antagonists were as effective as scopolamine in decreasing immobility in the forced swim test, a preclinical indicator of potential antidepressant activity. However, at equieffective or even larger doses, they were considerably less disruptive than scopolamine in assays of cognition-related behavior. All three drugs displayed high specificity for the mAChRs with few off-target binding sites, and CJ2100 showed modest affinity across the mAChRs when compared with L-687,306 and scopolamine. These data emphasize the dissimilar pharmacological profiles that are evident across antimuscarinic compounds and the potential utility of novel antagonists for the improved treatment of depression. SIGNIFICANCE STATEMENT: Some clinical studies with the muscarinic antagonist scopolamine document its ability to produce antidepressant effects in patients with mood disorders; however, scopolamine also has well known adverse effects on both autonomic and centrally mediated physiological functions that limit its therapeutic use. This study characterizes the cardiovascular and discriminative stimulus effects of two novel muscarinic antagonists, L-687,306 and CJ2100, that produce antidepressant-like effects in a rodent model (forced swim test) without affecting touchscreen-based cognitive performance (titrating psychomotor vigilance and delayed matching-to-position).

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The emergence of drug resistance, coupled with the issue of low tumor selectivity and toxicity is a major pitfall in cancer chemotherapy. It has necessitated the urgent need for the discovery of less toxic and more potent new anti-cancer pharmaceuticals, which target the interactive mechanisms involved in division and metastasis of cancer cells. Human DNA ligase I (hligI) plays an important role in DNA replication by linking Okazaki fragments on the lagging strand of DNA, and also participates in DNA damage repair processes. Dysregulation of the functioning of such ligases can severely impact DNA replication and repair pathways events that are generally targeted in cancer treatment. Although, several human DNA ligase inhibitors have been reported in the literature but unfortunately not a single inhibitor is currently being used in cancer chemotherapy. Results of pre-clinical studies also support the fact that human DNA ligases are an attractive target for the development of new anticancer agents which work by the selective inhibition of rapidly proliferating cancer cells. In this manuscript, we discuss, in brief, the structure, synthesis, structure-activity-relationship (SAR) and anticancer activity of recently reported hLigI inhibitors.

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A rapid, transition metal-free, high-yielding, tetrabutylammonium bromide-promoted method of N-arylation is reported within. The optimized conditions tolerated a wide range of secondary amines and was equally effective with bromo- and chlorobenzene-including substituted aryl halides. The developed method is found to be effective for N-arylation when compared to earlier methods which involve harsh conditions, transition metals, lack of scalability, and long reaction times. Our method utilizes conventional heating only; it is readily scalable; and the products are facile to purify.

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BACKGROUND: Nerve stimulation for regional anesthesia can be modeled mathematically. The authors present a mathematical framework to model the underlying electrophysiology, the development of software to implement that framework, and examples of simulation results. METHODS: The mathematical framework includes descriptions of the needle, the resulting potential field, and the active nerve fiber. The latter requires a model of the individual membrane ionic currents. The model geometry is defined by a three-dimensional coordinate system that allows the needle to be manipulated as it is clinically and tracked in relation to the nerve fiber. The skin plane is included as an electrical boundary to current flow. The mathematical framework was implemented in the Matlab (The MathWorks, Natick, MA) computing environment and organized around a graphical user interface. Simulations were performed using an insulated needle or an uninsulated needle inserted perpendicular to the skin with the nerve fiber at a depth of 2 cm. For each needle design, data were obtained with the needle as cathode or anode. Data are presented as current-distance maps that highlight combinations of current amplitude and tip-to-nerve distance that evoked a propagated response. RESULTS: With the needle tip positioned 2 mm proximal to the depth of the nerve, an insulated needle required a current greater than 0.457 mA for impulse propagation when attached to the cathode; when attached to the anode, the minimal current was 2.354 mA. In the same position, an uninsulated needle attached to the cathode required a current greater than 2.395 mA to generate a response. However, when an uninsulated needle was attached to the anode, currents up to 7 mA were inadequate to produce a propagated response. Of particular interest were combinations of current amplitude and needle position that activated the fiber but blocked impulse propagation for cathodal stimulation. CONCLUSIONS: Mathematical modeling of nerve stimulation for regional anesthesia is possible and could be used to investigate new equipment or needle designs, test nerve localization protocols, enhance clinical and experimental data, and ultimately generate new hypotheses.

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Atrial fibrillation (AF) is the most common arrhythmia in clinical practice. Most in vivo experimental research on AF is performed in a surgical setting, on animals instrumented by external devices, or using commercial implantable pacemakers. This paper describes a novel implantable cardiac telemetry system, which allows the study of AF remotely in conscious and ambulatory animals over a few month period. To validate this concept, the system was built and implanted in a sheep for 3 months. During this period, the system was used to deliver chronic rapid atrial pacing for AF induction, and to record and measure atrial electrograms and atrial effective refractory period (AERP) daily. During the course of AF induction the AERP decreased, confirming the progression of the electrical remodeling process in the atria. Episodes of paroxysmal AF were successfully induced in the animal. Burst pacing therapy was delivered with the system, however, no AF termination was observed. Result shows that this telemetry-based pacing and monitoring system can be used to study AF in a conscious animal non-invasively for an extended period of time, making this system a unique research tool.

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UNLABELLED: Extracellular Stimuli in an Atrial Reentrant Loop. INTRODUCTION: The interactions between extracellular stimuli and excitation waves propagating in a reentrant loop are a complex function of stimulus parameters, structural properties, membrane state, and timing. Here the goal was a comprehensive understanding of the mechanisms and frequencies of the major interactions between the advancing excitation wave and a single extracellular stimulus, separated from issues of anatomic or geometric complexity. METHODS AND RESULTS: A modernized computer model of a thin ring of uniform tissue that included a pair of extracellular stimulus electrodes (anode/cathode) was used to model one-dimensional cardiac reentry. Questions and results included the following: (1) What are the major interactions between a stimulus and the reentrant propagation wave, and are they induced near the cathode or near the anode; and, for each interaction, what are the initiating amplitude range and timing interval? At the cathode, the well-known mechanism of retrograde excitation terminated reentry; changes in timing or amplitude produced double-wave reentry or phase reset. At the anode, termination occurred at different cells depending on stimulus amplitude. (2) Relatively how often did termination occur at the anode? For most stimulus amplitudes, termination occurred more often at the anode than at the cathode, although not always at the same cell. (3) With random timing, what is the probability of terminating reentry? Stimulation for 5 msec terminated reentry with a probability from 0% to approximately 10%, as a function of increasing stimulus amplitude. CONCLUSION: A single extracellular stimulus can initiate major changes in reentrant excitation via multiple mechanisms, even in a simple geometry. Termination of reentry, phase shifts, or double-wave reentry each occurs over well-defined ranges of stimulus amplitude and timing.

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Core-conductor models, used to integrate the behavior of the longitudinal currents with the distributed voltages of electrically active tissue, have evolved for over a century. A critical step in the use of such models is the computation of membrane current from the set of distributed transmembrane potential values that exist at a given moment, where the potentials are obtained either experimentally or computationally. Over time, interest has developed in a number of substantial extensions of the original model to include such features as nonuniform spatial resistances, loop instead of linear structure, and multiple sites of extracellular stimulation. This paper concisely restates and extends the equations for calculation of transmembrane currents with the systematic inclusion of alternative cases, noting how they reduce to the standard forms. An important issue is how complex the calculation of membrane current has to be. Thus, the paper goes on to show criteria (based on the uniformity of resistance and the presence of stimulation) for deciding when membrane currents can be obtained with a relatively simple calculation with a single equation involving local variables versus with a more complex calculation involving the simultaneous solution of a (possibly large) set of equations.

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