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Trends in Pharmacological Sciences Jul 2008Ischemic cardiovascular events represent the leading cause of mortality and morbidity worldwide, and platelet aggregation and thrombus formation are the main effectors... (Review)
Review
Ischemic cardiovascular events represent the leading cause of mortality and morbidity worldwide, and platelet aggregation and thrombus formation are the main effectors of acute arterial ischemic events. Although antiplatelet therapy is the cornerstone of antithrombotic treatment of ischemic cardiovascular disorders, available antiplatelet agents have less than satisfactory efficacy; thus, the identification of novel potential target candidates for antiplatelet therapy is highly warranted. Recent evidence suggests that several molecules that amplify the aggregation response of platelets to activating stimuli, which are either released by platelets (potentiating molecules) or present in the milieu before platelets get activated (primers), play a major role in pathologic thrombus formation without being significantly involved in primary haemostasis. These molecules appear to be a particularly appealing novel potential pharmacologic target for antiplatelet therapy. Here, we review the present knowledge on some molecules acting as potentiators or primers of platelet activation and discuss their possible pharmacologic modulation for antithrombotic purposes.
Topics: Animals; CD40 Ligand; Dinoprostone; Humans; Leptin; Matrix Metalloproteinase 2; Matrix Metalloproteinase Inhibitors; Platelet Activation; Platelet Aggregation Inhibitors; Vascular Endothelial Growth Factor A
PubMed: 18539343
DOI: 10.1016/j.tips.2008.05.002 -
Critical Reviews in Food Science and... 1983This review provides extensive presentation and evaluation of data relative to flavor potentiation, including the historical, chemical, organoleptic, metabolic,... (Review)
Review
This review provides extensive presentation and evaluation of data relative to flavor potentiation, including the historical, chemical, organoleptic, metabolic, physiological, and consumptive properties of the commonly available flavor potentiators, which are primarily monosodium glutamate and 5'-nucleotides. In addition, their food occurrences, mode of action, manufacturing procedures, and methods of analyses will be discussed. Also, attention will be given to miscellaneous compounds that possess flavor potentiating properties.
Topics: Adolescent; Adult; Animals; Beer; Chemical Phenomena; Chemistry, Physical; Child; Child, Preschool; Dairy Products; Drug Stability; Feeding Behavior; Fish Products; Flavoring Agents; Glutamates; Glutamic Acid; Guanosine Monophosphate; Humans; Infant; Infant, Newborn; Inosine Monophosphate; Meat Products; Milk, Human; Nucleic Acid Conformation; Sodium Glutamate; Structure-Activity Relationship; Taste; Taste Threshold; Tongue; Vegetables
PubMed: 6137322
DOI: 10.1080/10408398309527364 -
European Journal of Medicinal Chemistry May 2023Major depressive disorder is a common psychiatric disorder, with ∼30% of patients suffering from treatment-resistant depression. Based on preclinical studies on...
Major depressive disorder is a common psychiatric disorder, with ∼30% of patients suffering from treatment-resistant depression. Based on preclinical studies on ketamine, α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor (AMPAR) activation may be a promising therapeutic approach. In this study, we synthesized a series of novel 3,4-dihydrobenzo[e][1,2,3]oxathiazine 2,2-dioxide analogs and analyzed their potential as AMPAR potentiators. Compounds 5aa and 7k exhibited high potentiation with little agonist activity in a high-throughput screen using a calcium influx assay in cultured hippocampal primary neurons. In rats, compound 7k had better pharmacokinetic properties and oral bioavailability (F = 67.19%); it also exhibited an acceptable safety profile in vital internal organs based on hematoxylin and eosin staining. We found that 7k produced a rapid antidepressant-like effect in chronic restraint stress-induced mice 1 h after intraperitoneal administration. Our study presented a series of novel AMPAR potentiators and identified 7k as a promising drug-like candidate against major depressive disorders.
Topics: Rats; Mice; Animals; Receptors, AMPA; Depressive Disorder, Major; Antidepressive Agents; Ketamine; Neurons
PubMed: 36924669
DOI: 10.1016/j.ejmech.2023.115252 -
BioRxiv : the Preprint Server For... Mar 2024The cystic fibrosis transmembrane conductance regulator (CFTR) is a crucial ion channel whose loss of function leads to cystic fibrosis, while its hyperactivation leads...
The cystic fibrosis transmembrane conductance regulator (CFTR) is a crucial ion channel whose loss of function leads to cystic fibrosis, while its hyperactivation leads to secretory diarrhea. Small molecules that improve CFTR folding (correctors) or function (potentiators) are clinically available. However, the only potentiator, ivacaftor, has suboptimal pharmacokinetics and inhibitors have yet to be clinically developed. Here we combine molecular docking, electrophysiology, cryo-EM, and medicinal chemistry to identify novel CFTR modulators. We docked ~155 million molecules into the potentiator site on CFTR, synthesized 53 test ligands, and used structure-based optimization to identify candidate modulators. This approach uncovered novel mid-nanomolar potentiators as well as inhibitors that bind to the same allosteric site. These molecules represent potential leads for the development of more effective drugs for cystic fibrosis and secretory diarrhea, demonstrating the feasibility of large-scale docking for ion channel drug discovery.
PubMed: 37745391
DOI: 10.1101/2023.09.09.557002 -
The Journal of Physiology Oct 19821. The contractility (maximum rate of rise of left ventricular pressure) and action potential duration were measured in intact closed-chest anaesthetized dogs with...
1. The contractility (maximum rate of rise of left ventricular pressure) and action potential duration were measured in intact closed-chest anaesthetized dogs with complete atrioventricular dissociation and beta-adrenergic blockade.2. Measurements were confined to test beats following a 1 sec interval. Prior to the test interval (priming period) a variety of potentiating stimulus trains were introduced.3. When the frequency of stimulation was increased in the priming period (frequency potentiation), there was an inverse relationship between action potential duration and contractility of the test beat.4. When the test beat was potentiated by a single beat terminating the priming period with one short interval (post-extrasystolic potentiation), there was no relationship between the action potential duration and contractility of the test beat.5. Paired pulse stimulation was used for any given frequency to vary contractility by short interval potentiation. For any given frequency of stimulation there was no relationship between action potential duration and contractility of the test beat. For any given value of contractility, action potential duration decreased with increased frequency of stimulation.6. The introduction of a high frequency train caused a step decrease in action potential duration on the first beat of the train. This was followed by a further slow decline in action potential duration with a time course of over 3 min. These two changes could be dissociated by the introduction during the train of one second interval test pulses, which only showed the slow shortening.7. The lack of a consistent relationship between action potential duration and contractility of the test beat disagrees with the hypothesis that repolarization is controlled by the activator calcium responsible for the contractility. The action potential shortening associated with increased frequency is related to the frequency change per se.8. The slow time course of change in action potential duration following an increase in stimulation frequency suggests that these changes are caused by the accumulation of an ion or metabolite, or possibly by changes of activity of the electrogenic Na(+)-K(+) pump.
Topics: Action Potentials; Animals; Dogs; Electric Stimulation; Heart; Myocardial Contraction; Time Factors
PubMed: 7153914
DOI: 10.1113/jphysiol.1982.sp014386 -
Journal of Cystic Fibrosis : Official... Jan 2021F508del is prototypical of Class 2 CFTR mutations associated with protein misprocessing and reduced function. Corrector compounds like lumacaftor partially rescue the...
BACKGROUND
F508del is prototypical of Class 2 CFTR mutations associated with protein misprocessing and reduced function. Corrector compounds like lumacaftor partially rescue the processing defect of F508del-CFTR whereas potentiators like ivacaftor, enhance its channel activity once trafficked to the cell surface. We asked if emerging modulators developed for F508del-CFTR can rescue Class 2 mutations previously shown to be poorly responsive to lumacaftor and ivacaftor.
METHODS
Rescue of mutant CFTRs by the correctors: AC1, AC2-1 or AC2-2 and the potentiator, AP2, was studied in HEK-293 cells and in primary human nasal epithelial (HNE) cultures, using a membrane potential assay and Ussing chamber, respectively.
RESULTS
In HEK-293 cells, we found that a particular combination of corrector molecules (AC1 plus AC2-1) and a potentiator (AP2) was effective in rescuing both the misprocessing and reduced function of M1101K and G85E respectively. These findings were recapitulated in patient-derived nasal cultures, although another corrector combination, AC1 plus AC2-2 also improved misprocessing in these primary tissues. Interestingly, while this corrector combination only led to a modest increase in the abundance of mature N1303K-CFTR it did enable its functional expression in the presence of the potentiator, AP2, in part, because the nominal corrector, AC2-2 also exhibits potentiator activity.
CONCLUSIONS
Strategic combinations of novel modulators can potentially rescue Class 2 mutants thought to be relatively unresponsive to lumacaftor and ivacaftor.
Topics: Aminophenols; Aminopyridines; Benzodioxoles; Cells, Cultured; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Drug Combinations; Drug Evaluation, Preclinical; Drug Resistance; Humans; Mutation; Quinolones
PubMed: 32741662
DOI: 10.1016/j.jcf.2020.07.015 -
The Journal of Neuroscience : the... Dec 2020A major driver of obesity is the increasing palatability of processed foods. Although reward circuits promote the consumption of palatable food, their involvement in...
A major driver of obesity is the increasing palatability of processed foods. Although reward circuits promote the consumption of palatable food, their involvement in obesity remains unclear. The ventral pallidum (VP) is a key hub in the reward system that encodes the hedonic aspects of palatable food consumption and participates in various proposed feeding circuits. However, there is still no evidence for its involvement in developing diet-induced obesity. Here we examine, using male C57BL6/J mice and patch-clamp electrophysiology, how chronic high-fat high-sugar (HFHS) diet changes the physiology of the VP and whether mice that gain the most weight differ in their VP physiology from others. We found that 10-12 weeks of HFHS diet hyperpolarized and decreased the firing rate of VP neurons without a major change in synaptic inhibitory input. Within the HFHS group, the top 33% weight gainers (WGs) had a more hyperpolarized VP with longer latency to fire action potentials on depolarization compared with bottom 33% of weight gainers (i.e., non-weight gainers). WGs also showed synaptic potentiation of inhibitory inputs both at the millisecond and minute ranges. Moreover, we found that the tendency to potentiate the inhibitory inputs to the VP might exist in overeating mice even before exposure to HFHS, thus making it a potential property of being an overeater. These data point to the VP as a critical player in obesity and suggest that hyperpolarized membrane potential of, and potentiated inhibitory inputs to, VP neurons may play a significant role in promoting the overeating of palatable food. In modern world, where highly palatable food is readily available, overeating is often driven by motivational, rather than metabolic, needs. It is thus conceivable that reward circuits differ between obese and normal-weight individuals. But is such difference, if it exists, innate or does it develop with overeating? Here we reveal synaptic properties in the ventral pallidum, a central hub of reward circuits, that differ between mice that gain the most and the least weight when given unlimited access to highly palatable food. We show that these synaptic differences also exist without exposure to palatable food, potentially making them innate properties that render some more susceptible than others to overeat. Thus, the propensity to overeat may have a strong innate component embedded in reward circuits.
Topics: Action Potentials; Animals; Basal Forebrain; Body Weight; Diet; Male; Mice; Neuronal Plasticity; Neurons; Obesity; Patch-Clamp Techniques; Reward; Weight Gain
PubMed: 33199503
DOI: 10.1523/JNEUROSCI.1809-20.2020 -
Current Opinion in Chemical Biology Feb 2022Because of the rise in antibiotic resistance and the dwindling pipeline of effective antibiotics, it is imperative to explore avenues that breathe new life into existing... (Review)
Review
Because of the rise in antibiotic resistance and the dwindling pipeline of effective antibiotics, it is imperative to explore avenues that breathe new life into existing drugs. This is particularly important for intrinsically resistant Gram-negative bacteria, which are exceedingly difficult to treat. The Gram-negative outer membrane (OM) prevents the entry of a plethora of antibiotics that are effective against Gram-positive bacteria, despite the presence of the targets of these drugs. Uncovering molecules that increase the permeability of the OM to sensitize Gram-negative bacteria to otherwise ineffective antibiotics is an approach that has recently garnered increased attention in the field. In this review, we survey chemical matter which has been shown to potentiate antibiotics against Gram-negative bacteria by perturbing the OM. These include peptides, nanoparticles, macromolecules, antibiotic conjugates, and small molecules.
Topics: Anti-Bacterial Agents; Gram-Negative Bacteria
PubMed: 34808425
DOI: 10.1016/j.cbpa.2021.102099 -
Biochimica Et Biophysica Acta.... Feb 2017The membrane dipole potential (Ψ) constitutes one of three electrical potentials generated by cell membranes. Ψ arises from the unfavorable parallel alignment of...
The membrane dipole potential (Ψ) constitutes one of three electrical potentials generated by cell membranes. Ψ arises from the unfavorable parallel alignment of phospholipid and water dipoles, and varies in magnitude both longitudinally and laterally across the bilayer according to membrane composition and phospholipid packing density. In this work, we propose that dynamic counter-balancing between Ψ and the transmembrane potential (ΔΨ) governs the conformational state transitions of voltage-gated ion channels. Ψ consists of 1) static outer, and dynamic inner leaflet components (Ψ and Ψ, respectively); and 2) a transmembrane component (ΔΨ), ariing from differences in intra- and extracellular leaflet composition. Ψ, which transitions between high and low energy states (Ψ and Ψ) as a function of channel conformation, is transduced by the pore domain. ΔΨ is transduced by the voltage-sensing (VS) domain in summation with ΔΨ. Potentiation of voltage-gated ion channels is of interest for the treatment of cardiac, neuronal, and other disorders arising from inherited/acquired ion channel dysfunction. Potentiators are widely believed to alter the rates and voltage-dependencies of channel gating transitions by binding to pockets in the membrane-facing and other regions of ion channel targets. Here, we propose that potentiators alter Ψ and/or Ψ, thereby increasing or decreasing the energy barriers governing channel gating transitions. We used quantum mechanical and molecular dynamics (MD) simulations to predict the overall Ψ-modulating effects of a series of published positive hERG potentiators partitioned into model DOPC bilayers. Our findings suggest a strong correlation between the magnitude of Ψ-lowering and positive hERG potentiation across the series.
Topics: Binding Sites; Biophysical Phenomena; Cations; Cell Membrane; Humans; Ion Channel Gating; Ion Channels; Lipid Bilayers; Membrane Potentials; Molecular Dynamics Simulation; Protein Binding; Transcriptional Regulator ERG
PubMed: 27836643
DOI: 10.1016/j.bbamem.2016.11.005 -
MBio Aug 2023Each year, fungi cause more than 1.5 billion infections worldwide and have a devastating impact on human health, particularly in immunocompromised individuals or...
Each year, fungi cause more than 1.5 billion infections worldwide and have a devastating impact on human health, particularly in immunocompromised individuals or patients in intensive care units. The limited antifungal arsenal and emerging multidrug-resistant species necessitate the development of new therapies. One strategy for combating drug-resistant pathogens is the administration of molecules that restore fungal susceptibility to approved drugs. Accordingly, we carried out a screen to identify small molecules that could restore the susceptibility of pathogenic species to azole antifungals. This screening effort led to the discovery of novel 1,4-benzodiazepines that restore fluconazole susceptibility in resistant isolates of , as evidenced by 100-1,000-fold potentiation of fluconazole activity. This potentiation effect was also observed in azole-tolerant strains of and in other pathogenic species. The 1,4-benzodiazepines selectively potentiated different azoles, but not other approved antifungals. A remarkable feature of the potentiation was that the combination of the compounds with fluconazole was fungicidal, whereas fluconazole alone is fungistatic. Interestingly, the potentiators were not toxic to in the absence of fluconazole, but inhibited virulence-associated filamentation of the fungus. We found that the combination of the potentiators and fluconazole significantly enhanced host survival in a model of systemic fungal infection. Taken together, these observations validate a strategy wherein small molecules can restore the activity of highly used anti-infectives that have lost potency. IMPORTANCE In the last decade, we have been witnessing a higher incidence of fungal infections, due to an expansion of the fungal species capable of causing disease (e.g., ), as well as increased antifungal drug resistance. Among human fungal pathogens, species are a leading cause of invasive infections and are associated with high mortality rates. Infections by these pathogens are commonly treated with azole antifungals, yet the expansion of drug-resistant isolates has reduced their clinical utility. In this work, we describe the discovery and characterization of small molecules that potentiate fluconazole and restore the susceptibility of azole-resistant and azole-tolerant isolates. Interestingly, the potentiating 1,4-benzodiazepines were not toxic to fungal cells but inhibited their virulence-associated filamentous growth. Furthermore, combinations of the potentiators and fluconazole decreased fungal burdens and enhanced host survival in a model of systemic fungal infections. Accordingly, we propose the use of novel antifungal potentiators as a powerful strategy for addressing the growing resistance of fungi to clinically approved drugs.
Topics: Humans; Antifungal Agents; Candida; Fluconazole; Azoles; Pharmaceutical Preparations; Microbial Sensitivity Tests; Candida albicans; Mycoses; Drug Resistance, Fungal; Benzodiazepines
PubMed: 37326546
DOI: 10.1128/mbio.00479-23