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2. Synthesis of rearranged indole diterpenes of the paxilline type

Author

Schatz, Devon J, Kuenstner, Eric J, George, David T, and Pronin, Sergey V

Subjects
Organic Chemistry, Chemical Sciences, Infectious Diseases, Biological Products, Diterpenes, Indoles, Biological Sciences, Medical and Health Sciences, Medicinal and biomolecular chemistry, Traditional, complementary and integrative medicine
Abstract

Covering: up to 2021Rearranged indole diterpenes of the paxilline type comprise a large group of fungal metabolites that possess diverse structural features and potentially useful biological effects. The unique indoloterpenoid motif, which is common to all congeners, was first confirmed by crystallographic studies of paxilline. This family of natural products has fascinated organic chemists for the past four decades and has inspired numerous syntheses and synthetic approaches. The present review highlights efforts that have laid the foundation and introduced new directions to this field of natural product synthesis. The introduction includes a summary of biosynthetic considerations and biological activities, the main body of the manuscript provides a detailed discussion of selected syntheses, and the review concludes with a brief outlook on the future of the field.

Published
2022

4. Alcohol effects on globus pallidus connectivity: Role of impulsivity and binge drinking

Author

Fede, Samantha J, Abrahao, Karina P, Cortes, Carlos R, Grodin, Erica N, Schwandt, Melanie L, George, David T, Diazgranados, Nancy, Ramchandani, Vijay A, Lovinger, David M, and Momenan, Reza

Subjects
Biological Psychology, Pharmacology and Pharmaceutical Sciences, Biomedical and Clinical Sciences, Psychology, Underage Drinking, Basic Behavioral and Social Science, Neurosciences, Substance Misuse, Clinical Research, Pediatric, Alcoholism, Alcohol Use and Health, Mental Health, Behavioral and Social Science, Aetiology, 2.3 Psychological, social and economic factors, 2.1 Biological and endogenous factors, Cardiovascular, Oral and gastrointestinal, Cancer, Stroke, Good Health and Well Being, Adult, Binge Drinking, Connectome, Female, Globus Pallidus, Humans, Impulsive Behavior, Magnetic Resonance Imaging, Male, Middle Aged, Stress, Psychological, General Science & Technology
Abstract

Despite the harm caused by binge drinking, the neural mechanisms leading to risky and disinhibited intoxication-related behaviors are not well understood. Evidence suggests that the globus pallidus externus (GPe), a substructure within the basal ganglia, participates in inhibitory control processes, as examined in stop-signaling tasks. In fact, studies in rodents have revealed that alcohol can change GPe activity by decreasing neuronal firing rates, suggesting that the GPe may have a central role in explaining impulsive behaviors and failures of inhibition that occur during binge drinking. In this study, twenty-five healthy volunteers underwent intravenous alcohol infusion to achieve a blood alcohol level of 0.08 g/dl, which is equivalent to a binge drinking episode. A resting state functional magnetic resonance imaging scan was collected prior to the infusion and at binge-level exposure. Functional connectivity analysis was used to investigate the association between alcohol-induced changes in GPe connectivity, drinking behaviors, and impulsivity traits. We found that individuals with greater number of drinks or heavy drinking days in the recent past had greater alcohol-induced deficits in GPe connectivity, particularly to the striatum. Our data also indicated an association between impulsivity and alcohol-induced deficits in GPe-frontal/precentral connectivity. Moreover, alcohol induced changes in GPe-amygdala circuitry suggested greater vulnerabilities to stress-related drinking in some individuals. Taken together, these findings suggest that alcohol may interact with impulsive personality traits and drinking patterns to drive alterations in GPe circuitry associated with behavioral inhibition, possibly indicating a neural mechanism by which binge drinking could lead to impulsive behaviors.

Published
2020

5. A Radical-Polar Crossover Annulation To Access Terpenoid Motifs

Author

Thomas, William P, Schatz, Devon J, George, David T, and Pronin, Sergey V

Subjects
Inorganic Chemistry, Organic Chemistry, Chemical Sciences, Colforsin, Stereoisomerism, Terpenes, General Chemistry, Chemical sciences, Engineering
Abstract

A new catalytic radical-polar crossover annulation between two unsaturated carbonyl compounds is described. The annulation proceeds under exceptionally mild conditions and provides direct and expedient access to complex terpenoid motifs. Application of this chemistry allows for synthesis of forskolin, a densely functionalized terpenoid, in 14 steps from commercially available material.

Published
2019

8. A Concise Approach to Paxilline Indole Diterpenes

Author

George, David T, Kuenstner, Eric J, and Pronin, Sergey V

Subjects
Diterpenes, Indoles, Molecular Structure, Terpenes, Chemical Sciences, General Chemistry
Abstract

A synthetic approach to paxilline indole diterpenes is described. The route to the pentacyclic core relies on a new regioselective alkenylation of ketones and a tandem radical addition-aldol reaction sequence to access vicinal quaternary stereocenters. Emindole SB, the simplest member of the family, is synthesized in 11 steps from commercially available material to demonstrate the application of this approach.

Published
2015

10. Safety and feasibility clinical trial of nucleus accumbens deep brain stimulation for treatment-refractory opioid use disorder

Author

Rezai, Ali R., primary, Mahoney, James J., additional, Ranjan, Manish, additional, Haut, Marc W., additional, Zheng, Wanhong, additional, Lander, Laura R., additional, Berry, James H., additional, Farmer, Daniel L., additional, Marton, Jennifer L., additional, Tirumalai, Padma, additional, Mears, Ashley, additional, Thompson-Lake, Daisy G. Y., additional, Finomore, Victor S., additional, D’Haese, Pierre-François, additional, Aklin, Will M., additional, George, David T., additional, Corrigan, John D., additional, and Hodder, Sally L., additional

Published
2024
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25. Effect of acamprosate on magnetic resonance spectroscopy measures of central glutamate in detoxified alcohol-dependent individuals: a randomized controlled experimental medicine study

Author

Umhau, John C., Momenan, Reza, Schwandt, Melanie L., Singley, Erick, Lifshitz, Mariel, Doty, Linda, Adams, Lauren J., Vengeliene, Valentina, Spanagel, Rainer, Zhang, Yan, Shen, Jun, George, David T., Hommer, Daniel, and Heilig, Markus

Subjects
Acamprosate -- Dosage and administration, Acamprosate -- Research, Glutamate -- Physiological aspects, Glutamate -- Research, Magnetic resonance imaging -- Research, Alcoholism -- Care and treatment, Alcoholism -- Research, Health, Psychology and mental health
Published
2010

33. Common Factors Underlying Diverse Responses in Alcohol Use Disorder

Author

Chebolu, Esha, primary, Schwandt, Melanie L., additional, Ramchandani, Vijay A., additional, Stangl, Bethany L., additional, George, David T., additional, Horneffer, Yvonne, additional, Vinson, Tonette, additional, Vogt, Emily L., additional, Manor, Brandon A., additional, Diazgranados, Nancy, additional, and Goldman, David, additional

Published
2021
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40. PPAR gamma activation by pioglitazone does not suppress cravings for alcohol, and is associated with a risk of myopathy in treatment seeking alcohol dependent patients: a randomized controlled proof of principle study

Author

Schwandt, Melanie L., Diazgranados, Nancy, Umhau, John C., Kwako, Laura E., George, David T., Heilig, Markus, Schwandt, Melanie L., Diazgranados, Nancy, Umhau, John C., Kwako, Laura E., George, David T., and Heilig, Markus

Abstract

Rationale Proinflammatory processes have been implicated in alcohol addiction, craving, and relapse, while studies in experimental animals have suggested that activation of peroxisome proliferator-activated receptor gamma (PPAR gamma) inhibits proinflammatory signaling. Accordingly, it is hypothesized that medications with PPAR gamma activity may have therapeutic potential in alcohol dependence. Objectives We conducted a double-blind, placebo-controlled mechanistic proof of principle study in alcohol-dependent inpatients to investigate the effect of pioglitazone on alcohol craving. Methods Participants were treated for withdrawal, if needed, and then randomized to pioglitazone (target dose 45 mg/day) or placebo. Once at target dose, they completed two experimental manipulations: guided imagery, which used personalized auditory scripts to induce alcohol cravings, and a low-dose challenge with i.v. lipopolysaccharide (LPS; 0.8 ng/kg) or placebo, on two separate sessions, in counterbalanced order. Behavioral and endocrine responses as well as CSF levels of proinflammatory cytokines were evaluated. Results The study was prematurely terminated after randomization of 16 subjects, following an independent review that established a high risk of myopathy in the active treatment group. Analysis of those who completed the study indicated that pioglitazone was associated with elevated, rather than suppressed alcohol cravings in response to alcohol-associated stimuli. LPS did not induce cravings for alcohol and thus did not lend itself to evaluating pioglitazone effects; however, pioglitazone increased the neuroendocrine stress response to LPS. CSF levels of IL-6, TNF-alpha, or MCP-1 were unaffected by pioglitazone treatment. Conclusions Both safety and efficacy biomarker data suggest that pioglitazone lacks potential as a medication for the treatment of alcohol dependence., Funding Agencies|NIH/NIAAA intramural program

Published
2020
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44. The physician's unique role in preventing violence: a neglected opportunity?

Author

Umhau John C, Trandem Karysse, Shah Mohsin, and George David T

Subjects
aggression, alcoholism, psychopharmacology, violence, domestic abuse, prevention, neurobiology, treatment, domestic violence, Medicine
Abstract

Abstract Background Episodes of explosive rage and violence comprise a symptom complex which can have a devastating effect on a person's life. In the community this behavior is seen as workplace violence, domestic abuse and road rage, while in the clinical setting, this behavior is rarely mentioned by patients, despite evidence that it can signify an important biological disorder that may afflict more than three percent of the population. Discussion Patients are often reluctant to seek help for episodic attacks of rage, especially attacks which are accompanied by physical violence. Although, in the past, clinicians have had few treatment options to offer, recent neuroscience advances have created new possibilities to understand and help patients with this neglected problem. No formal medical guidelines for treating violence exist; however, many patients can be helped by diagnosis, referral and treatment. Treatment can include pharmaceuticals and nutrients, as well as referral for anger management or behavioral therapy. Summary The astute clinician has an opportunity to positively impact an important problem through the diagnosis and treatment of patients with symptoms of intermittent explosive disorder.

Published
2012
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