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Chemical Communications (Cambridge,... May 2023Herein, we describe an effective strategy for enantioselective synthesis of oxindoles having a C3-quaternary stereocenter N-heterocyclic carbene (NHC) catalyzed...
Herein, we describe an effective strategy for enantioselective synthesis of oxindoles having a C3-quaternary stereocenter N-heterocyclic carbene (NHC) catalyzed desymmetrization of diols. The process is based on the catalytic asymmetric transfer acylation of primary alcohols using readily available aldehydes as an acylation agent. The reaction enables easy access to diversely functionalized C3-quaternary oxindoles with excellent enantioselectivity. The synthetic potential of the process is further demonstrated the preparation of the key intermediate for (-)-esermethole and (-)-physostigmine.
PubMed: 37096372
DOI: 10.1039/d3cc00489a -
Journal of Pineal Research Aug 2023Arylacetamide deacetylase (AADAC) is a deacetylation enzyme present in the mammalian liver, gastrointestinal tract, and brain. During our search for mammalian enzymes...
Arylacetamide deacetylase (AADAC) is a deacetylation enzyme present in the mammalian liver, gastrointestinal tract, and brain. During our search for mammalian enzymes capable of metabolizing N-acetylserotonin (NAS), AADAC was identified as having the ability to convert NAS to serotonin. Both human and rodent recombinant AADAC proteins can deacetylate NAS in vitro, although the human AADAC shows markedly higher activity compared with rodent enzyme. The AADAC-mediated deacetylation reaction can be potently inhibited by eserine in vitro. In addition to NAS, recombinant hAADAC can deacetylate melatonin (to form 5-methoxytryptamine) and N-acetyltryptamine (NAT) (to form tryptamine). In addition to the in vitro deacetylation of NAS by the recombinant AADAC proteins, liver (mouse and human) and brain (human) extracts were able to deacetylate NAS; these activities were sensitive to eserine. Taken together, these results demonstrate a new role for AADAC and suggest a novel pathway for the AADAC-mediated metabolism of pineal indoles in mammals.
Topics: Animals; Humans; Mice; Carboxylic Ester Hydrolases; Mammals; Melatonin; Physostigmine; Serotonin
PubMed: 37002641
DOI: 10.1111/jpi.12870 -
The American Journal of Emergency... May 2023Antimuscarinic delirium (AD), a potentially life-threatening condition frequently encountered by emergency physicians, results from poisoning with antimuscarinic agents....
INTRODUCTION
Antimuscarinic delirium (AD), a potentially life-threatening condition frequently encountered by emergency physicians, results from poisoning with antimuscarinic agents. Treatment with physostigmine and benzodiazepines is the mainstay of pharmacotherapy, and use of dexmedetomidine and non-physostigmine centrally-acting acetylcholinesterase inhibitors (cAChEi) such as rivastigmine has also been described. Unfortunately, these medications are subject to drug shortages which negatively impact the ability to provide appropriate pharmacologic treatment of patients with AD.
METHODS
Drug shortage data were retrieved from the University of Utah Drug Information Service (UUDIS) database from January 2001 through December 2021. Shortages of first-line agents used to treat AD (physostigmine and parenteral benzodiazepines) and second-line agents (dexmedetomidine and non-physostigmine cAChEi) were examined. Drug class, formulation, route of administration, reason for shortage, shortage duration, generic status, and whether the drug was a single-source product (made by only one manufacturer) were extracted. Shortage overlap and median shortage durations were calculated.
RESULTS
Twenty-six shortages impacting drugs used to treat AD were reported to UUDIS from January 1, 2001 to December 31, 2021. Median shortage duration for all medication classes was 6.0 months. Four shortages were unresolved at the end of the study period. The single medication most often on shortage was dexmedetomidine, however benzodiazepines were the most common medication class on shortage. Twenty-five shortages involved parenteral formulations, and one shortage involved the transdermal patch formulation of rivastigmine. The majority (88.5%) of shortages involved generic medications, and 50% of products on shortage were single-source. The most common reported reason for shortage was a manufacturing issue (27%). Shortages were often prolonged and, in 92% of cases, overlapped temporally with other shortages. Shortage frequency and duration increased during the second half of the study period.
CONCLUSION
Shortages of agents used in the treatment of AD were common during the study period and affected all agent classes. Shortages were often prolonged and multiple shortages were ongoing at study period end. Multiple concurrent shortages involving different agents occurred, which could hamper substitution as a means of mitigating shortage. Healthcare stakeholders must develop innovative patient- and institution-specific solutions in times of shortage and work to build resilience into the medical product supply chain to minimize future shortages of drugs used for treatment of AD.
Topics: Humans; Muscarinic Antagonists; Acetylcholinesterase; Dexmedetomidine; Rivastigmine; Drugs, Generic; Benzodiazepines; Delirium
PubMed: 36893630
DOI: 10.1016/j.ajem.2023.02.036 -
Bulletin of Experimental Biology and... Feb 2023The effect of dose-dependent activation of cholinoreactive structures on the severity of sinus bradycardia occurring in some intact newborn rats during the first weeks...
The effect of dose-dependent activation of cholinoreactive structures on the severity of sinus bradycardia occurring in some intact newborn rats during the first weeks after birth was analyzed in non-narcotized one-day-old (P1) and 16-day-old (P16) rats. The parameters of low-amplitude bradycardic oscillations of heart rhythm in norm and after administration of the acetylcholinesterase inhibitor physostigmine (eserine) in different doses (/, /, and /LD) to rats were studied. The maximum increase in the power of low-amplitude brady-cardic oscillations was achieved during moderate activation of cholinoreactive structures after injection of eserine in a dose of /LD. Further increase in acetylcholine level led to disappearance of the sinus rhythm and development of pathological bradycardia. The data obtained indicate the immaturity of the mechanisms of heart rhythm regulation in rats immediately after birth. During activation of cholinoreactive structures, the severity of bradycardia oscillations increases exponentially at P1 and has an inverse exponential character at P16, which indicates a high risk of cardiac rhythmogenesis disorders and dysrhythmia development in newborn rats under conditions of excessive enhancement of cholinergic activation.
Topics: Rats; Animals; Physostigmine; Bradycardia; Choline; Acetylcholinesterase; Cholinesterase Inhibitors
PubMed: 36879132
DOI: 10.1007/s10517-023-05721-5 -
The Journal of Pharmacology and... May 2023Optimization of effort-related choices is impaired in depressive disorders. Acetylcholine (ACh) and dopamine (DA) are linked to depressive disorders, and modulation of...
Optimization of effort-related choices is impaired in depressive disorders. Acetylcholine (ACh) and dopamine (DA) are linked to depressive disorders, and modulation of ACh tone in the ventral tegmental area (VTA) affects mood-related behavioral responses in rats. However, it is unknown if VTA ACh mediates effort-choice behaviors. Using a task of effort-choice, rats can choose to lever press on a fixed-ratio 5 (FR5) schedule for a more-preferred food or consume freely available, less-preferred food. VTA administration of physostigmine (1 μg and 2 μg/side), a cholinesterase inhibitor, reduced FR5 responding for the more-preferred food while leaving consumption of the less-preferred food intact. VTA infusion of the M5 muscarinic receptor negative allosteric modulator VU6000181 (3 μM, 10 μM, 30 μM/side) did not affect lever pressing or chow consumption. However, VU6000181 (30 μM/side) coadministration with physostigmine (2 μg/side) attenuated physostigmine-induced decrease in lever pressing in female and male rats and significantly elevated lever pressing above vehicle baseline levels in male rats. In in vivo voltammetry experiments, VTA infusion of combined physostigmine and VU6000181 did not significantly alter evoked phasic DA release in the nucleus accumbens core (NAc) in female rats. In male rats, combined VTA infusion of physostigmine and VU6000181 increased phasic evoked DA release in the NAc compared with vehicle, physostigmine, or VU6000181 infusion alone. These data indicate a critical role and potential sex differences of VTA M5 receptors in mediating VTA cholinergic effects on effort choice behavior and regulation of DA release. SIGNIFICANCE STATEMENT: Effort-choice impairments are observed in depressive disorders, which are often treatment resistant to currently available thymoleptics. The role of ventral tegmental area (VTA) acetylcholine muscarinic M5 receptors, in a preclinical model of effort-choice behavior, is examined. Using the selective negative allosteric modulator of the M5 receptor VU6000181, we show the role of VTA M5 receptors on effort-choice and regulation of dopamine release in the nucleus accumbens core. This study supports M5 receptors as therapeutic targets for depression.
Topics: Female; Rats; Male; Animals; Ventral Tegmental Area; Nucleus Accumbens; Dopamine; Receptor, Muscarinic M5; Acetylcholine; Physostigmine; Rats, Sprague-Dawley
PubMed: 36828630
DOI: 10.1124/jpet.122.001438 -
Die Anaesthesiologie Mar 2023Impaired consciousness is a frequent phenomenon after general anesthesia. In addition to the classical causes (e.g., overhang of sedatives), an impairment of... (Review)
Review
Impaired consciousness is a frequent phenomenon after general anesthesia. In addition to the classical causes (e.g., overhang of sedatives), an impairment of consciousness can also be an adverse side effect of drugs. Many drugs used in anesthesia can trigger these symptoms. Alkaloids, such as atropine can trigger a central anticholinergic syndrome, opioids can promote the occurrence of serotonin syndrome and the administration of a neuroleptic can lead to neuroleptic malignant syndrome. These three syndromes are difficult to diagnose due to the individually very heterogeneous symptoms. Mutual symptoms, such as impaired consciousness, tachycardia, hypertension and fever further complicate the differentiation between the syndromes; however, more individual symptoms, such as sweating, muscle tension or bowl sounds can be helpful in distinguishing these syndromes. The time from the trigger event can also help to differentiate the syndromes. The central anticholinergic syndrome is the fastest to appear, usually taking just a few of hours from trigger to clinical signs, serotonin syndrome takes several hours up to 1 day to show and neuroleptic malignant syndrome usually takes days. The clinical symptoms can range from mild to life-threatening. Generally, mild cases are treated with discontinuation of the trigger and extended observation. More severe cases can require specific antidotes. The specific treatment recommended for central anticholinergic syndrome is physostigmine with an initial dose of 2 mg (0.04 mg/kg body weight, BW) administered over 5 min. For serotonin syndrome an initial dose of 12 mg cyproheptadine followed by 2 mg every 2 h is recommended (maximum 32 mg/day or 0.5 mg/kgBW day) but this medication is only available in Germany as an oral formulation. For neuroleptic malignant syndrome 25-120 mg dantrolene (1-2.5 mg/kgBW maximum 10 mg/kgBW day) is the recommended treatment.
Topics: Humans; Neuroleptic Malignant Syndrome; Antipsychotic Agents; Serotonin Syndrome; Diagnosis, Differential; Cholinergic Antagonists; Anticholinergic Syndrome; Consciousness; Drug-Related Side Effects and Adverse Reactions
PubMed: 36799968
DOI: 10.1007/s00101-023-01256-6 -
Neuropsychopharmacology : Official... Mar 2023The cholinergic system is a critical mediator of cognition in animals. People who smoke cigarettes exhibit cognitive deficits, especially during quit attempts. Few...
The cholinergic system is a critical mediator of cognition in animals. People who smoke cigarettes exhibit cognitive deficits, especially during quit attempts. Few studies jointly examine the cholinergic system and cognition in people while trying to quit smoking. We used positron emission tomography (PET) brain imaging with the β-subunit containing nicotinic acetylcholine receptor (β*-nAChR) partial agonist radioligand (-)-[F]flubatine and the acetylcholinesterase inhibitor physostigmine to jointly examine the cholinergic system, smoking status, and cognition. (-)-[F]Flubatine scans and cognitive data were acquired from twenty people who recently stopped smoking cigarettes (aged 38 ± 11 years; 6 female, 14 male; abstinent 7 ± 1 days) and 27 people who never smoked cigarettes (aged 29 ± 8 years; 11 female, 16 male). A subset of fifteen recently abstinent smokers and 21 never smokers received a mid-scan physostigmine challenge to increase acetylcholine levels. Regional volume of distribution (V) was estimated with equilibrium analysis at "baseline" and post-physostigmine. Participants completed a cognitive battery prior to (-)-[F]flubatine injection and physostigmine administration assessing executive function (Groton Maze Learning test), verbal learning (International Shopping List test), and working memory (One Back test). Physostigmine significantly decreased cortical (-)-[F]flubatine V, consistent with increased cortical acetylcholine levels reducing the number of β*-nAChR sites available for (-)-[F]flubatine binding, at comparable magnitudes across groups (p values < 0.05). A larger magnitude of physostigmine-induced decrease in (-)-[F]flubatine V was significantly associated with worse executive function in people who recently stopped smoking (p values < 0.05). These findings underscore the role of the cholinergic system in early smoking cessation and highlight the importance of neuroscience-informed treatment strategies.
Topics: Animals; Male; Female; Acetylcholine; Acetylcholinesterase; Physostigmine; Positron-Emission Tomography; Brain; Receptors, Nicotinic; Cognition; Cholinergic Agents; Smoking
PubMed: 36681758
DOI: 10.1038/s41386-023-01535-1 -
Chemico-biological Interactions Feb 2023Phthalates are widely used plasticizers that are primarily and rapidly metabolized to monoester phthalates in mammals. In the present study, the hydrolysis of dibutyl...
Hydrolysis of dibutyl phthalate and di(2-ethylhexyl) phthalate in human liver, small intestine, kidney, and lung: An in vitro analysis using organ subcellular fractions and recombinant carboxylesterases.
Phthalates are widely used plasticizers that are primarily and rapidly metabolized to monoester phthalates in mammals. In the present study, the hydrolysis of dibutyl phthalate (DBP) and di(2-ethylhexyl) phthalate (DEHP) in the human liver, small intestine, kidney, and lung was examined by the catalytic, kinetic, and inhibition analyses using organ microsomal and cytosolic fractions and recombinant carboxylesterases (CESs). The V (y-intercept) values based on the Eadie-Hofstee plots of DBP hydrolysis were liver > small intestine > kidney > lung in microsomes, and liver > small intestine > lung > kidney in cytosol, respectively. The CL values (x-intercept) were small intestine > liver > kidney > lung in both microsomes and cytosol. The V and CL or CL values of DEHP hydrolysis were small intestine > liver > kidney > lung in both microsomes and cytosol. Bis(4-nitrophenyl) phosphate (BNPP) effectively inhibited the activities of DBP and DEHP hydrolysis in the microsomes and cytosol of liver, small intestine, kidney, and lung. Although physostigmine also potently inhibited DBP and DEHP hydrolysis activities in both the microsomes and cytosol of the small intestine and kidney, the inhibitory effects in the liver and lung were weak. In recombinant CESs, the V values of DBP hydrolysis were CES1 (CES1b, CES1c) > CES2, whereas the CL values were CES2 > CES1 (CES1b, CES1c). On the other hand, the V and CL values of DEHP hydrolysis were CES2 > CES1 (CES1b, CES1c). These results suggest an extensive organ-dependence of DBP and DEHP hydrolysis due to CES expression, and that CESs are responsible for the metabolic activation of phthalates.
Topics: Animals; Humans; Dibutyl Phthalate; Carboxylic Ester Hydrolases; Diethylhexyl Phthalate; Hydrolysis; Liver; Intestine, Small; Microsomes; Kidney; Lung; Mammals
PubMed: 36657734
DOI: 10.1016/j.cbi.2023.110353