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Journal of the American Chemical Society Nov 2022This paper describes a catalytic asymmetric Staudinger-aza-Wittig reaction of (-azidoaryl)malonates, allowing access to chiral quaternary oxindoles through phosphine...
This paper describes a catalytic asymmetric Staudinger-aza-Wittig reaction of (-azidoaryl)malonates, allowing access to chiral quaternary oxindoles through phosphine oxide catalysis. We designed a novel HypPhos oxide catalyst to enable the desymmetrizing Staudinger-aza-Wittig reaction through the P/P═O redox cycle in the presence of a silane reductant and an Ir-based Lewis acid. The reaction occurs under mild conditions, with good functional group tolerance, a wide substrate scope, and excellent enantioselectivity. Density functional theory revealed that the enantioselectivity in the desymmetrizing reaction arose from the cooperative effects of the Ir species and the HypPhos catalyst. The utility of this methodology is demonstrated by the (formal) syntheses of seven alkaloid targets: (-)-gliocladin C, (-)-coerulescine, (-)-horsfiline, (+)-deoxyeseroline, (+)-esermethole, (+)-physostigmine, and (+)-physovenine.
Topics: Oxindoles; Stereoisomerism; Oxides; Catalysis; Alkaloids
PubMed: 36375169
DOI: 10.1021/jacs.2c09421 -
Behavioural Brain Research Jul 2021There is high clinical interest in improving the pharmacological treatment of individuals with Major Depressive Disorder (MDD). This neuropsychiatric disorder continues...
There is high clinical interest in improving the pharmacological treatment of individuals with Major Depressive Disorder (MDD). This neuropsychiatric disorder continues to cause significant morbidity and mortality worldwide, where existing pharmaceutical treatments such as selective serotonin reuptake inhibitors often have limited efficacy. In a recent publication, we demonstrated an antidepressant-like role for the acetylcholinesterase inhibitor (AChEI) donepezil in the C57BL/6J mouse forced swim test (FST). Those data added to a limited literature in rodents and human subjects which suggests AChEIs have antidepressant properties, but added the novel finding that donepezil only showed antidepressant-like properties at lower doses (0.02, 0.2 mg/kg). At a high dose (2.0 mg/kg), donepezil tended to promote depression-like behavior, suggesting a u-shaped dose-response curve for FST immobility. Here we investigate the effects of three other AChEIs with varying molecular structures: galantamine, physostigmine, and rivastigmine, to test whether they also exhibit antidepressant-like effects in the FST. We find that these drugs do exhibit therapeutic-like effects at low but not high doses, albeit at lower doses for physostigmine. Further, we find that their antidepressant-like effects are not mediated by generalized hyperactivity in the novel open field test, and are also not accompanied by anxiolytic-like properties. These data further support the hypothesis that acetylcholine has a u-shaped dose-response relationship with immobility in the C57BL/6J mouse FST, and provide a rationale for more thoroughly investigating whether reversible AChEIs as a class can be repurposed for the treatment of MDD in human subjects.
Topics: Animals; Antidepressive Agents; Association Learning; Behavior, Animal; Cholinesterase Inhibitors; Donepezil; Dose-Response Relationship, Drug; Drug Repositioning; Galantamine; Male; Mice; Mice, Inbred C57BL; Motor Activity; Physostigmine; Rivastigmine; Swimming
PubMed: 33910028
DOI: 10.1016/j.bbr.2021.113323 -
Clinical Case Reports May 2022Hyoscine butylbromide-induced pyschosis, though rare, should be considered in a child presenting with deteriorating cognitive functions and psychotic features acutely as...
Hyoscine butylbromide-induced pyschosis, though rare, should be considered in a child presenting with deteriorating cognitive functions and psychotic features acutely as evident in our case of a 9-year-old child taking hyoscine for her non-specific abdominal pain.
PubMed: 35540718
DOI: 10.1002/ccr3.5807 -
Behavioural Brain Research Jun 2021Deficits in olfaction are associated with neurodegenerative disorders such as Alzheimer's disease. A recent study reported that intranasal zinc sulfate (ZnSO)-treated...
Deficits in olfaction are associated with neurodegenerative disorders such as Alzheimer's disease. A recent study reported that intranasal zinc sulfate (ZnSO)-treated mice show olfaction and memory deficits. However, it remains unknown whether olfaction deficit-induced learning and memory impairment is associated with the cholinergic system in the brain. In this study, we evaluated olfactory function by the buried food find test, and learning and memory function by the Y-maze and passive avoidance tests in ZnSO-treated mice. The expression of choline acetyltransferase (ChAT) protein in the olfactory bulb (OB), prefrontal cortex, hippocampus, and amygdala was assessed by western blotting. Moreover, we observed the effect of the acetylcholinesterase inhibitor physostigmine on ZnSO-induced learning and memory deficits. We found that intranasal ZnSO-treated mice exhibited olfactory dysfunction, while this change was recovered on day 14 after treatment. Both short-term and long-term learning and memory were impaired on days 4 and 7 after treatment with ZnSO, whereas the former, but not the latter, was recovered on day 14 after treatment. A significant correlation was observed between olfactory function and short-term memory, but not long-term memory. Treatment with ZnSO decreased the ChAT level in the OB on day 4, and increased and decreased the ChAT levels in the OB and hippocampus on day 7, respectively. Physostigmine improved the ZnSO-induced deficit in short-term, but not long-term, memory. Taken together, the present results suggest that short-term memory may be closely associated with olfactory function via the cholinergic system.
Topics: Animals; Astringents; Choline O-Acetyltransferase; Cholinesterase Inhibitors; Disease Models, Animal; Hippocampus; Male; Memory Disorders; Memory, Long-Term; Memory, Short-Term; Mice; Olfaction Disorders; Olfactory Bulb; Physostigmine; Zinc Sulfate
PubMed: 33819530
DOI: 10.1016/j.bbr.2021.113283 -
Sleep Jun 2020The synaptic homeostasis theory of sleep proposes that low neurotransmitter activity in sleep optimizes memory consolidation. We tested this theory by asking whether...
The synaptic homeostasis theory of sleep proposes that low neurotransmitter activity in sleep optimizes memory consolidation. We tested this theory by asking whether increasing acetylcholine levels during early sleep would weaken motor memory consolidation. We trained separate groups of adult mice on the rotarod walking task and the single pellet reaching task, and after training, administered physostigmine, an acetylcholinesterase inhibitor, to increase cholinergic tone in subsequent sleep. Post-sleep testing showed that physostigmine impaired motor skill acquisition of both tasks. Home-cage video monitoring and electrophysiology revealed that physostigmine disrupted sleep structure, delayed non-rapid-eye-movement sleep onset, and reduced slow-wave power in the hippocampus and cortex. Additional experiments showed that: (1) the impaired performance associated with physostigmine was not due to its effects on sleep structure, as 1 h of sleep deprivation after training did not impair rotarod performance, (2) a reduction in cholinergic tone by inactivation of cholinergic neurons during early sleep did not affect rotarod performance, and (3) stimulating or blocking muscarinic and nicotinic acetylcholine receptors did not impair rotarod performance. Taken together, the experiments suggest that the increased slow wave activity and inactivation of both muscarinic and nicotinic receptors during early sleep due to reduced acetylcholine contribute to motor memory consolidation.
Topics: Acetylcholine; Animals; Memory Consolidation; Mice; Physostigmine; Sleep; Sleep Deprivation
PubMed: 31825510
DOI: 10.1093/sleep/zsz297 -
Deutsche Medizinische Wochenschrift... Feb 2020While monitoring and symptomatic care is sufficient for most intoxicated patients, some develop life threatening symptoms. We present recent changes in the...
While monitoring and symptomatic care is sufficient for most intoxicated patients, some develop life threatening symptoms. We present recent changes in the recommendations of the treatment in patients with calcium channel blocker, beta blocker and high dose paracetamol intoxications. Additionally, new insights in the efficacy and safety of the use of physostigmine in anticholinergic patients and beta blockers in cocaine intoxication are discussed as well as the specific considerations in the resuscitation of intoxicated patients.
Topics: Acetaminophen; Adrenergic beta-Antagonists; Calcium Channel Blockers; Carbon; Critical Care; Humans; Physostigmine; Poisoning
PubMed: 32018289
DOI: 10.1055/a-0965-3203 -
Journal of Experimental & Clinical... Dec 2020Nerve-cancer interactions are increasingly recognized to be of paramount importance for the emergence and progression of pancreatic cancer (PCa). Here, we investigated...
BACKGROUND
Nerve-cancer interactions are increasingly recognized to be of paramount importance for the emergence and progression of pancreatic cancer (PCa). Here, we investigated the role of indirect cholinergic activation on PCa progression through inhibition of acetylcholinesterase (AChE) via clinically available AChE-inhibitors, i.e. physostigmine and pyridostigmine.
METHODS
We applied immunohistochemistry, immunoblotting, MTT-viability, invasion, flow-cytometric-cell-cycle-assays, phospho-kinase arrays, multiplex ELISA and xenografted mice to assess the impact of AChE inhibition on PCa cell growth and invasiveness, and tumor-associated inflammation. Survival analyses were performed in a novel genetically-induced, surgically-resectable mouse model of PCa under adjuvant treatment with gemcitabine+/-physostigmine/pyridostigmine (n = 30 mice). Human PCa specimens (n = 39) were analyzed for the impact of cancer AChE expression on tumor stage and survival.
RESULTS
We discovered a strong expression of AChE in cancer cells of human PCa specimens. Inhibition of this cancer-cell-intrinsic AChE via pyridostigmine and physostigmine, or administration of acetylcholine (ACh), diminished PCa cell viability and invasion in vitro and in vivo via suppression of pERK signaling, and reduced tumor-associated macrophage (TAM) infiltration and serum pro-inflammatory cytokine levels. In the novel genetically-induced, surgically-resectable PCa mouse model, adjuvant co-therapy with AChE blockers had no impact on survival. Accordingly, survival of resected PCa patients did not differ based on tumor AChE expression levels. Patients with higher-stage PCa also exhibited loss of the ACh-synthesizing enzyme, choline-acetyltransferase (ChAT), in their nerves.
CONCLUSION
For future clinical trials of PCa, direct cholinergic stimulation of the muscarinic signaling, rather than indirect activation via AChE blockade, may be a more effective strategy.
Topics: Acetylcholine; Adult; Aged; Aged, 80 and over; Animals; Apoptosis; Cell Cycle; Cell Movement; Cell Proliferation; Choline O-Acetyltransferase; Cholinergic Agents; Female; Humans; Inflammation; Male; Mice; Middle Aged; Neoplasm Invasiveness; Pancreatic Neoplasms; Prognosis; Survival Rate; Tumor Cells, Cultured; Xenograft Model Antitumor Assays
PubMed: 33357230
DOI: 10.1186/s13046-020-01796-4 -
Angewandte Chemie (International Ed. in... Jun 2021Reductive carboxylation of organo (pseudo)halides with CO is a powerful method to provide carboxylic acids quickly. Notably, the catalytic reductive carbo-carboxylation...
Reductive carboxylation of organo (pseudo)halides with CO is a powerful method to provide carboxylic acids quickly. Notably, the catalytic reductive carbo-carboxylation of unsaturated hydrocarbons via CO fixation is a highly challenging but desirable approach for structurally diverse carboxylic acids. There are only a few reports and no examples of alkenes via transition metal catalysis. We report the first asymmetric reductive carbo-carboxylation of alkenes with CO via nickel catalysis. A variety of aryl (pseudo)halides, such as aryl bromides, aryl triflates and inert aryl chlorides of particular note, undergo the reaction smoothly to give important oxindole-3-acetic acid derivatives bearing a C3-quaternary stereocenter. This transformation features mild reaction conditions, wide substrate scope, facile scalability, good to excellent chemo-, regio- and enantioselectivities. The method highlights the formal synthesis of (-)-Esermethole, (-)-Physostigmine and (-)-Physovenine, and the total synthesis of (-)-Debromoflustramide B, (-)-Debromoflustramine B and (+)-Coixspirolactam A; thereby, opening an avenue for the total synthesis of chiral natural products with CO .
PubMed: 33793030
DOI: 10.1002/anie.202102769 -
European Journal of Case Reports in... 2024Sudden onset of reduced consciousness, psychomotor agitation and mydriasis are all indicative of an anticholinergic toxidrome. It is important to note that numerous...
INTRODUCTION
Sudden onset of reduced consciousness, psychomotor agitation and mydriasis are all indicative of an anticholinergic toxidrome. It is important to note that numerous drugs, as well as certain herbs and plants, possess anticholinergic properties.
CASE DESCRIPTION
An 84-year-old female patient had sudden nocturnal onset of uncoordinated hand movements and altered mental status. Shortly after, the patient's 83-year-old husband developed symptoms of dysarthria, gait ataxia, vertigo, and delirium.
CONCLUSION
Anticholinergic syndrome consists of a combination of central and peripheral anticholinergic symptoms. Physostigmine given intravenously resulted in rapid reversal of symptoms. Thorn apple seeds had been accidentally ingested and were identified as the cause.
LEARNING POINTS
The clinical presentation of an anticholinergic toxidrome includes both central and peripheral symptoms such as altered consciousness, mydriasis, dry mucous membranes and skin, and tachycardia.Prompt recognition of anticholinergic toxidrome and the administration of physostigmine can lead to rapid reversal of symptoms and improved patient outcomes.Treatment with physostigmine is indicated when a patient with an agitated delirium does not respond adequately to titrated benzodiazepines.
PubMed: 38584905
DOI: 10.12890/2024_004381 -
Neuropharmacology Jul 2020Acetylcholine is implicated in mood disorders including depression and anxiety. Increased cholinergic tone in humans and rodents produces pro-depressive and...
Acetylcholine is implicated in mood disorders including depression and anxiety. Increased cholinergic tone in humans and rodents produces pro-depressive and anxiogenic-like effects. Cholinergic receptors in the ventral tegmental area (VTA) are known to mediate these responses in male rats, as measured by the sucrose preference test (SPT), elevated plus maze (EPM), and the forced swim test (FST). However, these effects have not been examined in females, and the VTA muscarinic receptor subtype(s) mediating the pro-depressive and anxiogenic-like behavioral effects of increased cholinergic tone are unknown. We first examined the behavioral effects of increased VTA cholinergic tone in male and female rats, and then determined whether VTA muscarinic M5 receptors were mediating these effects. VTA infusion of the acetylcholinesterase inhibitor physostigmine (0.5 μg, 1 μg and 2 μg/side) in males and females produced anhedonic-like, anxiogenic, pro-depressive-like responses on the SPT, EPM, and FST. In females, VTA administration of the muscarinic M5 selective negative allosteric modulator VU6000181 (0.68 ng, 2.3 ng, 6.8 ng/side for a 3 μM, 10 μM, 30 μM/side infusion) did not alter SPT, EPM nor FST behavior. However, in males intra-VTA infusion of VU6000181 alone reduced time spent immobile on the FST. Furthermore, co-infusion of VU6000181 with physostigmine, in male and female rats, attenuated the pro-depressive and anxiogenic-like behavioral responses induced by VTA physostigmine alone, in the SPT, EPM, and FST. Together, these data reveal a critical role of VTA M5 receptors in mediating the anhedonic, anxiogenic, and depressive-like behavioral effects of increased cholinergic tone in the VTA.
Topics: Anhedonia; Animals; Anxiety; Behavior, Animal; Cholinergic Agents; Cholinesterase Inhibitors; Depression; Female; Male; Muscarinic Agonists; Muscarinic Antagonists; Physostigmine; Rats; Rats, Sprague-Dawley; Receptor, Muscarinic M5; Swimming; Ventral Tegmental Area
PubMed: 32268153
DOI: 10.1016/j.neuropharm.2020.108089