Design, Synthesis, and In Vivo Evaluation of C1-Linked 4,5-Epoxymorphinan Haptens for Heroin Vaccines.

In our continuing effort to develop effective anti-heroin vaccines as potential medications for the treatment of opioid use disorder, herein we present the design and synthesis of the haptens: 1-AmidoMorHap (1), 1-AmidoMorHap epimer (2), 1 Amido-DihydroMorHap (3), and 1 Amido-DihydroMorHap epimer (4). This is the first report of hydrolytically stable haptenic surrogates of heroin with the attachment site at the C1 position in the 4,5-epoxymorophinan nucleus. We prepared respective tetanus toxoid (TT)-hapten conjugates as heroin vaccine immunogens and evaluated their efficacy in vivo. We showed that all TT-hapten conjugates induced high antibody endpoint titers against the targets but only haptens 2 and 3 can induce protective effects against heroin in vivo. The epimeric analogues of these haptens, 1 and 4, failed to protect mice from the effects of heroin. We also showed that the in vivo efficacy is consistent with the results of the in vitro drug sequestration assay. Attachment of the linker at the C1 position induced antibodies with weak binding to the target drugs. Only TT-2 and TT-3 yielded antibodies that bound heroin and 6-acetyl morphine. None of the TT-hapten conjugates induced antibodies that cross-reacted with morphine, methadone, naloxone, or naltrexone, and only TT-3 interacted weakly with buprenorphine, and that subtle structural difference, especially at the C6 position, can vastly alter the specificity of the induced antibodies. This study is an important contribution in the field of vaccine development against small-molecule targets, providing proof that the chirality at C6 in these epoxymorphinans is a vital key to their effectiveness.

Modulation of opioid receptor affinity and efficacy via N-substitution of 9ß-hydroxy-5-(3-hydroxyphenyl)morphan: Synthesis and computer simulation study.

The enantiomers of a variety of N-alkyl-, N-aralkyl-, and N-cyclopropylalkyl-9ß-hydroxy-5-(3-hydroxyphenyl)morphans were synthesized employing cyanogen bromide and K2CO3 to improve the original N-demethylation procedure. Their binding affinity to the µ-, δ-, and κ-opioid receptors (ORs) was determined and functional (GTPγ35S) assays were carried out on those with reasonable affinity. The 1R,5R,9S-enantiomers (1R,5R,9S)-(-)-5-(3-hydroxyphenyl)-2-(4-nitrophenethyl)-2-azabicyclo[3.3.1]nonan-9-ol (1R,5R,9S-16), (1R,5R,9S)-(-) 2-cinnamyl-5-(3-hydroxyphenyl)-2-azabicyclo[3.3.1]nonan-9-ol (1R,5R,9S-20), and (1R,5R,9S)-(-)-5-(3-hydroxyphenyl)-2-(4-(trifluoromethyl)phenethyl)-2-azabicyclo[3.3.1]nonan-9-ol (1R,5R,9S-15), had high affinity for the µ-opioid receptor (e.g., 1R,5R,9S-16: Ki=0.073, 0.74, and 1.99nM, respectively). The 1R,5R,9S-16 and 1R,5R,9S-15 were full, high efficacy µ-agonists (EC50=0.74 and 18.5nM, respectively) and the former was found to be a partial agonist at δ-OR and an antagonist at κ-OR, while the latter was a partial agonist at δ-OR and κ-OR in the GTPγ35S assay. The enantiomer of 1R,5R,9S-16, (+)-1S,5S,9R-16 was unusual, it had good affinity for the µ-OR (Ki=26.5nM) and was an efficacious µ-antagonist (Ke=29.1nM). Molecular dynamics simulations of the µ-OR were carried out with the 1R,5R,9S-16 µ-agonist and the previously synthesized (1R,5R,9S)-(-)-5-(9-hydroxy-5-(3-hydroxyphenyl-2-phenylethyl)-2-azabicyclo[3.3.1]nonane (1R,5R,9S-(-)-NIH 11289) to provide a structural basis for the observed high affinities and efficacies. The critical roles of both the 9ß-OH and the p-nitro group are elucidated, with the latter forming direct, persistent hydrogen bonds with residues deep in the binding cavity, and the former interacting with specific residues via highly structured water bridges.

Highly enantioselective carbonyl-ene reactions of 2,3-diketoesters: efficient and atom-economical process to functionalized chiral α-hydroxy-ß-ketoesters.

Carbonyl-ene reactions of 2,3-diketoesters catalyzed by [Cu{(S,S)-tBu-box}](SbF6)2 [box=bis(oxazoline)] generate chiral α-functionalized α-hydroxy-ß-ketoesters in up to 94% yield and 97% ee. The 2,3-diketoesters are conveniently accessed from the corresponding α-diazo-ß-ketoester, and a catalyst loading as low as 1.0 mol% can be achieved.

Optimization of the radiosynthesis of [(18) F]MEFWAY for imaging brain serotonin 1A receptors by using the GE TracerLab FXFN-Pro module.

The aim of this study was to develop a highly reliable radiofluorination method for the preparation of N-{2-[4-(2-methoxyphenyl)piperazinyl]ethyl}-N-(2-pyridyl)-N-(4-(18) F-fluoromethylcyclohexane)carboxamide ([(18) F]Mefway) by using a fully automated system. The optimal condition is composed of two parts. The extraction system of the trapped F-18 in the anion exchange resin (i.e., quaternary methylamine cartridge) is a complex of Kryptofix 2.2.2. (K222, 4 mg/0.9 mL methanol) and K2 CO3 (1 mg/0.1 mL H2 O). After removing the solvents, the trans-tosylated Mefway precursor (1 mg/0.5 mL acetonitrile) was reacted with dried K222-K[(18) F] at 100°C for 5 min. After purification and formulation, [(18) F]Mefway was obtained with 38 ± 2.4% (decay corrected, n = 34) radiochemical yield, a total synthesis time of 52 ± 3.4 min, specific activity was 120.6 ± 8.7 GBq/µmol at the end of synthesis and a radiochemical purity of 99%. According to the quality control tests, formulated [(18) F]Mefway is suitable to apply parenteral clinical application.

The Health Justice Policy Tracker: COVID-19 Policies To Advance Health Justice For Vulnerable Populations.

The rapid spread of COVID-19 throughout the world in early 2020 created unprecedented challenges for national governments. Policies developed during the early months of the pandemic, before the first mRNA vaccines were authorized for emergency use, provide a window into national governments' prioritization of populations that were particularly vulnerable. We developed the COVID-19 Health Justice Policy Tracker to capture and categorize these policies using a health justice lens. In this article we present the results of a preliminary analysis of the tracker data. The tracker focuses on policies for six population groups: children, the elderly, people with disabilities, migrant workers, incarcerated people, and people who were refugees or were seeking political asylum. It includes 610 policies, most targeting children and the elderly and providing financial support. National governments also prioritized measures such as policies to ensure access to mental health care and social services, digital and teleservices, continuity of children's education, and food security. The tracker provides a resource for researchers and policy makers seeking model language and tested policy approaches to advance health justice during future crises.

The emergence of political priority for addressing child sexual abuse in the United Kingdom.

BACKGROUND: Child sexual abuse (CSA) is widespread. Few countries, however, prioritize the issue. The United Kingdom is an exception, ranked first in its response to the issue in a 2019 country comparison. In 2015, Prime Minister David Cameron designated the issue one of three national threats. Funding commitments and policies to address CSA followed. OBJECTIVE: To investigate how CSA emerged as a national political priority in the United Kingdom, and to identify insights for proponents seeking to advance priority for addressing the issue. PARTICIPANTS AND SETTING: Documents were analyzed and semi-structured interviews conducted with actors in the United Kingdom central to CSA advocacy, research, and/or programming, as well as with policymakers. METHODS: Drawing on the multiple streams public policy model, a thematic analysis was conducted on collected documents (n = 160) and 21 interview transcripts. RESULTS: Our analysis delineates three critical developments that led to national prioritization for addressing CSA. First, high-profile scandals and the re-framing of CSA survivors as deserving of support raised public awareness of the problem. Second, champions concerned with CSA developed evidence-based and politically-feasible solutions. Third, the Prime Minister's concern and other political developments opened a policy window. CONCLUSIONS: The case provides insights for proponents on generating political priority for addressing CSA. Proponents need to (1) ensure survivors are not seen as culpable but rather as deserving of support, (2) be ready with solutions and (3) cultivate high-level political support, so that when policy windows open they can jump to push the issue onto the national agenda.

An efficient methodology to substituted furans via oxidation of functionalized α-diazo-ß-ketoacetates.

DMDO oxidation of functionalized α-diazo-ß-ketoacetates, formed by zinc triflate catalyzed Mukaiyama-aldol condensation of methyl diazoacetoacetate with aldehydes, occurred in quantitative yield to form dihydrofuranols that undergo acid catalyzed dehydration under mild conditions to generate 3-methoxyfuran-2-carboxylates in good yield.

Impact of Traumatic Brain Injury on Clinical Institute Withdrawal Assessment Use in Trauma Patients: A Descriptive Study.

BACKGROUND: Alcohol withdrawal syndrome (AWS) and traumatic brain injury (TBI) present with similar signs and symptoms, yet their treatment strategies differ greatly. AWS treatment includes the Clinical Institute Withdrawal Assessment (CIWA) protocol, which grades withdrawal signs and symptoms. A major purpose of CIWA is to guide the addition and titration of central nervous system (CNS) depressants, most commonly benzodiazepines. Conversely, best practice is to avoid these same CNS depressants in the setting of TBI. Thus, patients with TBI presenting with AWS risk may receive undesirable interventions that could worsen outcome. OBJECTIVE: To describe the relationship of TBI diagnosis with CIWA protocol scores and intervention implementation. DESIGN: Retrospective cohort observational study. SETTING: Single university-based, level one trauma center. PATIENTS: Three hundred seventy-five patients with head trauma or AWS classification, identified through the trauma center's trauma registry. INTERVENTIONS: CIWA protocol and related medication use. MAIN OUTCOME MEASURES: Frequency of elevated CIWA score, length of CIWA administration, and medication administration incidence were abstracted from patients' medical records. RESULTS: The percentage of elevated CIWA scores increased significantly with TBI severity, from 4.5%(0-60) in the No TBI group, up to 12.5% (0-36) in the Mild TBI group, 27.1% (0-57) in the Moderate TBI group, and 50.0% (14-77) in the Severe TBI group. Nominally, lorazepam use showed a similar pattern of escalation with TBI severity, but it did not reach statistical significance. Haloperidol use did significantly escalate with higher TBI severity. No group differences were observed for total lorazepam equivalents or length on the CIWA protocol. CONCLUSIONS: TBI diagnosis and higher TBI severity level correlate with higher CIWA scores, but neither increased nor decreased benzodiazepine usage was observed. Antipsychotic use did escalate with TBI diagnosis and severity. The risks versus benefits of minimizing benzodiazepines in patients with TBI who are at risk for AWS warrant future study.

Correlation between HIV and sexual behavior, drug use, trichomoniasis and candidiasis among female sex workers in a Mekong Delta province of Vietnam.

To determine the prevalence of HIV and correlates of HIV infection among female sex workers (FSWs) in Soc Trang province, Vietnam, a survey of 406 FSWs in Soc Trang province was conducted between May and August, 2003. The participants were interviewed, using a standardized interview, to obtain information about socio-demographic and behavioral characteristics, and gynecologic and sexually transmitted infection (STI) history. The prevalence of HIV was 3.3%. An increased risk for HIV was associated with ever using illicit drugs, direct sex work, early sexual debut, age of FSWs, and infection with candidiasis and trichomoniasis. Reduced likelihood of HIV was only associated with withdrawal as a contraceptive method. A strong association of HIV with drug use and candidiasis and trichomoniasis infection among FSWs was found. Needle/syringe exchange, STI treatment, and methadone programs targeting FSWs should be implemented, and should include 100% condom use promotion.

Catalytic conversion of diazocarbonyl compounds to imines: applications to the synthesis of tetrahydropyrimidines and ß-lactams.

The synthesis of α-carbonylimines by rhodium(II)-catalyzed reactions of α-diazoesters and organic azides has been developed and applied in hetero-Diels-Alder reactions to form highly functionalized tetrahydropyrimidines and in a one-pot, multicomponent transformation between aryldiazoacetates, p-anisyl azide, and an enonediazoacetate to produce ß-lactams in high yields and diastereoselectivities.

Palladium mediated ¹¹C-cyanation and characterization in the non-human primate brain of the novel mGluR5 radioligand [¹¹C]AZD9272.

INTRODUCTION: The aims of the present positron emission tomography (PET) study were to set up a system for (11)C-cyanation labeling of the selective mGluR5-antagonist [(11)C]AZD9272 and to perform the first in vivo characterization of [(11)C]AZD9272 binding in cynomolgus monkeys. METHODS: [(11)C]AZD9272 was labeled using palladium mediated (11)C-cyanation. Altogether seven PET measurements were performed in three cynomolgus monkeys including baseline and co-injection experiments with unlabelled AZD9272 (0.04 and 0.4 mg/kg). Radiometabolites in plasma were measured using HPLC. RESULTS: [(11)C]AZD9272 was prepared in over 50% incorporation yield from hydrogen [(11)C]cyanide in a total synthesis time of 45-50 min. The radiochemical purity of the radioligand in its final formulation was high (>99%) and the mean specific radioactivity was 47 GBq/ µmol (1278 Ci/mmol, n=7) calculated at end of bombardment (EOB). In the baseline measurements 10% of the total injected radioactivity was present in monkey brain at five minutes after i.v. injection. The radioactivity concentration was high in the caudate, cingulate gyrus and thalamus whereas it was moderate in the temporal cortex and lower for the cerebellum. After co-injection with cold AZD9272 the binding of [(11)C]AZD9272 was reduced in a dose-dependent fashion. Analysis of radiometabolites showed relatively slow metabolism and resulted only in hydrophilic radiometabolites. CONCLUSION: A fast and efficient method was developed to label AZD9272 with (11)C. PET-examination in Cynomolgus monkeys showed that [(11)C]AZD9272 entered the brain to a high extent, that binding was saturable and that the regional radioactivity pattern was in accordance with the known distribution of mGluR5. The results support further examination of [(11)C]AZD9272 binding in human subjects.

Tetrahydroquinolines and benzazepines through catalytic diastereoselective formal [4 + 2]-cycloaddition reactions between donor-acceptor cyclopropenes and imines.

Regio- and diastereoselective Lewis acid catalyzed cycloaddition reactions between imines and donor-acceptor cyclopropenes generated from silyl-protected enoldiazoacetates provide direct access to stable cyclopropane-fused tetrahydroquinolines and, with cyclopropane ring opening under mild conditions, to 1H-benzazipine derivatives.

Diazoacetoacetate enones for the synthesis of diverse natural product-like scaffolds.

Diazoacetoacetate enones are a new class of Michael acceptors that enable the efficient construction of natural product-like scaffolds. Through their Michael addition reactions, including those with silyl enol ethers, indoles, pyrroles, and amines, δ-functionalized diazoacetoacetates are formed in high yield and with overall operational efficiency. Subsequent catalytic dinitrogen extrusion reactions provide access to a diverse series of natural product-like carbo- and heterocyclic ring systems in only three steps from commercial materials.

Divergent stereocontrol of acid catalyzed intramolecular aldol reactions of 2,3,7-triketoesters: synthesis of highly functionalized cyclopentanones.

The intramolecular acid catalyzed aldol cyclization of 2,3,7-triketoesters formed from ζ-keto-α-diazo-ß-ketoesters provides highly functionalized cyclopentanones with good diastereoselectivity in high overall yields via kinetically controlled and stereodivergent catalytic processes. Lewis acid catalysis gives high selectivity for the 1,2-anti tetrasubstituted cyclopentanones, whereas Brønsted acid catalysis produces the corresponding 1,2-syn diastereomer.

In-target produced [11C]methane: Increased specific radioactivity.

The (14)N(rho, alpha)(11)C reaction on N(2)-O(2) or N(2)-H(2) gaseous systems as targets in proton bombardment allows for the production of [(11)C]CO(2) and [(11)C]CH(4.) We report the target production of [(11)C]CH(4) and the gas phase iodination to produce [(11)C]CH(3)I with high specific radioactivity (SA). SA was calculated for four different radiopharmaceuticals produced in-house from both target produced [(11)C]CO(2) and [(11)C]CH(4.) For [(11)C]raclopride we obtained an average SA of 3908 GBq/mumol (106000 Ci/mmol) at the end of bombardment for the last 52 productions, which is a 32-fold increase compared to when using the in-house [(11)C]CO(2) target.

A fully automated one-pot synthesis of [carbonyl-11C]WAY-100635 for clinical PET applications.

A fully automated synthesis of the important 5HT(1A) receptor radioligand, [carbonyl-(11)C]WAY-100635 (I), was developed based on the optimized one-pot "wet" synthesis procedure. A modern automated apparatus was constructed from commercially available components and operated via LabView software. In average, (906+/-525)MBq (n=94) of (I) was obtained from 40 min bombardment at 50 microA beam current within 50 min synthesis time. The specific radioactivity (SA) at the time of injection was (50.5+/-29.3)GBq/mumol (n=94).

Discovery and labeling of high-affinity 3,4-diarylpyrazolines as candidate radioligands for in vivo imaging of cannabinoid subtype-1 (CB1) receptors.

Imaging of cannabinoid subtype-1 (CB1) receptors in vivo with positron emission tomography (PET) is likely to be important for understanding their role in neuropsychiatric disorders and for drug development. Radioligands for imaging with PET are required for this purpose. We synthesized new ligands from a 3,4- diarylpyrazoline platform of which (-)-12a ((-)-3-(4-chlorophenyl)-N'-[(4-cyanophenyl)sulfonyl]-4-phenyl- 4,5-dihydro-1H-pyrazole-1-carboxamidine) was found to have high-affinity and selectivity for binding to CB1 receptors. (-)-12a and its lower affinity enantiomer ((+)-12a) were labeled with carbon-11 (t1/2 ) 20.4 min) using [11C]cyanide ion as labeling agent and evaluated as PET radioligands in cynomolgus monkeys. After injection of [11C](-)-12a, there was high uptake and retention of radioactivity across brain according to the rank order of CB1 receptor densities. The distomer, [11C](+)-12a, failed to give a sustained CB1 receptor-specific distribution. Polar radiometabolites of [11C](-)-12a appeared moderately slowly in plasma. Radioligand [11C](-)-12a is promising for the study of brain CB1 receptors and merits further investigation in human subjects.