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The inhibitory activity of coronaridine congeners on human (h) α4β2 and α7 nicotinic acetylcholine receptors (AChRs) is determined by Ca(2+) influx assays, whereas their effects on neurons in the ventral inferior (VI) aspect of the mouse... more
The inhibitory activity of coronaridine congeners on human (h) α4β2 and α7 nicotinic acetylcholine receptors (AChRs) is determined by Ca(2+) influx assays, whereas their effects on neurons in the ventral inferior (VI) aspect of the mouse medial habenula (MHb) are determined by patch-clamp recordings. The Ca(2+) influx results clearly establish that coronaridine congeners inhibit hα3β4 AChRs with higher selectivity compared to hα4β2 and hα7 subtypes, and with the following potency sequence, for hα4β2: (±)-18-methoxycoronaridine [(±)-18-MC]>(+)-catharanthine>(±)-18-methylaminocoronaridine [(±)-18-MAC] ∼ (±)-18-hydroxycoronaridine [(±)-18-HC]; and for hα7: (+)-catharanthine>(±)-18-MC>(±)-18-HC>(±)-18-MAC. Interestingly, the inhibitory potency of (+)-catharanthine (27±4μM) and (±)-18-MC (28±6μM) on MHb (VI) neurons was lower than that observed on hα3β4 AChRs, suggesting that these compounds inhibit a variety of endogenous α3β4* AChRs. In addition, the interaction of bupro...
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Research Interests: Neuroscience, Psychology, Chemistry, Long Term Potentiation, Kinetics, and 15 moreNeuropharmacology, Calcium, Medicine, Cell line, Humans, Mutation, Animals, Protein Conformation, Neurosciences, Patch Clamp, Agonist, Allosteric regulation, Cholinergic agents, positive allosteric modulators, and Pharmacology and pharmaceutical sciences
Barbiturate-induced anesthesia is a complex mechanism that probably involves several ligand-gated ion channel superfamilies. One of these superfamilies includes the archetypical nicotinic acetylcholine receptor (nAChR), in which... more
Barbiturate-induced anesthesia is a complex mechanism that probably involves several ligand-gated ion channel superfamilies. One of these superfamilies includes the archetypical nicotinic acetylcholine receptor (nAChR), in which barbiturates act as noncompetitive antagonists. In this regard, we used the Torpedo californica nAChR and a series of barbiturate analogs to characterize the barbiturate binding site(s) on this superfamily member. [(14)C]Amobarbital binds to one high-affinity (K(d) = 3.7 microM) and several (approximately 11) low-affinity (K(d) = 930 microM) sites on the resting and desensitized nAChRs, respectively. Characteristics of the barbiturate binding site on the resting nAChR include: (1) a tight structure-activity relationship. For example, the barbiturate isobarbital [5-ethyl-5'-(2-methylbutyl) barbituric acid] is >10-fold less potent than its formula isomer amobarbital [5-ethyl-5'-(3-methylbutyl) barbituric acid] in inhibiting [(14)C]amobarbital bindin...
Research Interests: Chemistry, Molecular Pharmacology, Medicine, Ion Channels, Molecular modeling, and 15 moreMolecular, Pubmed, Animals, Nicotinic Acetylcholine Receptors, Molecular Conformation, Amino Acid Sequence, Barbituric Acid, Neurosciences, Binding Site, Barbiturates, Amobarbital, Photoaffinity Labeling, Molecular Sequence Data, Cell Membrane, and Pharmacology and pharmaceutical sciences
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To determine the structural components underlying differences in affinity, potency, and selectivity of varenicline for several human (h) nicotinic acetylcholine receptors (nAChRs), functional and structural experiments were performed. The... more
To determine the structural components underlying differences in affinity, potency, and selectivity of varenicline for several human (h) nicotinic acetylcholine receptors (nAChRs), functional and structural experiments were performed. The Ca(2+) influx results established that: (a) varenicline activates (μM range) nAChR subtypes with the following rank sequence: hα7>hα4β4>hα4β2>hα3β4>hα1β1γδ; (b) varenicline binds to nAChR subtypes with the following affinity order (nM range): hα4β2~hα4β4>hα3β4>hα7>Torpedo α1β1γδ. The molecular docking results indicating that more hydrogen bond interactions are apparent for α4-containing nAChRs in comparison to other nAChRs may explain the observed higher affinity; and that (c) varenicline is a full agonist at hα7 (101%) and hα4β4 (93%), and a partial agonist at hα4β2 (20%) and hα3β4 (45%), relative to (±)-epibatidine. The allosteric sites found at the extracellular domain (EXD) of hα3β4 and hα4β2 nAChRs could explain the partia...
Research Interests: Chemical Engineering, Chemistry, Calcium, Medicine, Gene expression, and 15 moreBiological Sciences, Humans, Animals, Physical sciences, Nicotinic Acetylcholine Receptors, Hydrogen Bonding, Protein Secondary Structure Prediction, Pyridines, Protein isoforms, Protein Binding, Biochemistry and cell biology, Partial Agonist, Agonist, Allosteric regulation, and CHO cells
Research Interests: Chemistry, Medicine, Ion Channels, Molecular modeling, Cell line, and 15 moreHumans, EC, Nicotinic Acetylcholine Receptors, Calcium Signaling, Pyridines, Ec, Protein Conformation, Mecamylamine, Protein Binding, Conformational Change, Imipramine, Biochemistry and cell biology, ACHR, binding sites, and DMEM
Research Interests: Pharmacology, Chemistry, Calcium, Medicine, Patch-clamp and imaging techniques, and 15 moreHumans, Antidepressant, Animals, Nicotinic Acetylcholine Receptors, Alkaloids, Ciencias Biológicas, Epithelial cells, Radioligand Assay, Pyridines, Molecular Conformation, Biofísica, Imipramine, Agonist, torpedo ink, and Pharmacology and pharmaceutical sciences
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Research Interests: Biochemistry, Biophysics, Chemistry, Kinetics, Calcium, and 15 moreDrug Discovery, Medicine, Cell line, Humans, Mice, Animals, Nicotinic Acetylcholine Receptors, Muscles, Antidepressants, Electric Conductivity, Imipramine, Biochemistry and cell biology, Allosteric regulation, bupropion, and Medical biochemistry and metabolomics
Research Interests: Biochemistry, Chemistry, Magnetic Resonance Spectroscopy, Medicine, Humans, and 10 moreStereochemistry, Nicotinic Acetylcholine Receptors, Mecamylamine, Biochemistry and cell biology, Enantiomer, Allosteric regulation, binding sites, Medical biochemistry and metabolomics, stereoisomerism, and Protein subunits
Research Interests: Chemical Engineering, Chemistry, Medicine, Ion Channels, Molecular modeling, and 15 moreBiological Sciences, Computer Simulation, Animals, Staphylococcus aureus, Physical sciences, Tritium, Molecular weight, Amino Acid Sequence, Binding Site, Biochemistry and cell biology, Photoaffinity Labeling, Molecular Sequence Data, binding sites, Molecular dynamic, and Azides
Research Interests: Chemical Engineering, Biophysics, Chemistry, Biophysical Chemistry, Medicine, and 13 moreBiological Sciences, Animals, Physical sciences, Ibogaine, Phencyclidine, CHEMICAL SCIENCES, Receptor, Protein Binding, Biochemistry and cell biology, Cytisine, binding sites, Cholinergic antagonists, and torpedo ink
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Research Interests: Chemistry, Molecular Pharmacology, Medicine, Animals, Nicotinic Acetylcholine Receptors, and 11 moreTritium, Radioligand Binding Assay, Neurosciences, Binding Site, Crystal Violet, Dissociation Constant, Photoaffinity Labeling, Cell Membrane, torpedo ink, Pharmacology and pharmaceutical sciences, and In Vitro Techniques
The drimane sesquiterpenoids drimenin, cinnamolide, dendocarbin A, and polygodial were purified from the Canelo tree ( Drimys winteri) and chemically characterized by spectroscopic methods. The pharmacological activity of these natural... more
The drimane sesquiterpenoids drimenin, cinnamolide, dendocarbin A, and polygodial were purified from the Canelo tree ( Drimys winteri) and chemically characterized by spectroscopic methods. The pharmacological activity of these natural compounds were determined on hα4β2, hα3β4, and hα7 nicotinic acetylcholine receptors (AChRs) by Ca influx measurements. The results established that drimane sesquiterpenoids inhibit AChRs with the following selectivity: hα4β2 > hα3β4 > hα7. In the case of hα4β2 AChRs, the following potency rank order was determined (IC's in μM): drimenin (0.97 ± 0.35) > cinnamolide (1.57 ± 0.36) > polygodial (62.5 ± 19.9) ≫ dendocarbin A (no activity). To determine putative structural features underlying the differences in inhibitory potency at hα4β2 AChRs, additional structure-activity relationship and molecular docking experiments were performed. The Ca influx and structural results supported a noncompetitive mechanism of inhibition, where drimenin i...
Research Interests: Pharmacology, Biochemistry, Biophysics, Chemistry, Hematology, and 14 moreNatural Products, Cell Biology, Medicine, Biological Sciences, Ic, Stereochemistry, Ligand Binding, CHEMICAL SCIENCES, Inmunología, Inhibitor, Spectroscopic Methods, Structure activity Relationship, Potency, and Medical and Health Sciences
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Research Interests: Biochemistry, Thermodynamics, Chemistry, Medicine, Ion Channels, and 15 moreAnimals, Stereochemistry, Nicotinic Acetylcholine Receptors, Phencyclidine, Ciencias Biológicas, Tritium, Resting State, Structure activity Relationship, Protein Binding, Adamantane, Binding Site, Crystal Violet, Biochemistry and cell biology, binding sites, and Medical biochemistry and metabolomics
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It is generally assumed that selective serotonin reuptake inhibitors (SSRIs) induce antidepressant activity by inhibiting serotonin (5-HT) reuptake transporters, thus elevating synaptic 5-HT levels and, finally, ameliorates depression... more
It is generally assumed that selective serotonin reuptake inhibitors (SSRIs) induce antidepressant activity by inhibiting serotonin (5-HT) reuptake transporters, thus elevating synaptic 5-HT levels and, finally, ameliorates depression symptoms. New evidence indicates that SSRIs may also modulate other neurotransmitter systems by inhibiting neuronal nicotinic acetylcholine receptors (nAChRs), which are recognized as important in mood regulation. There is a clear and strong association between major depression and smoking, where depressed patients smoke twice as much as the normal population. However, SSRIs are not efficient for smoking cessation therapy. In patients with major depressive disorder, there is a lower availability of functional nAChRs, although their amount is not altered, which is possibly caused by higher endogenous ACh levels, which consequently induce nAChR desensitization. Other neurotransmitter systems have also emerged as possible targets for SSRIs. Studies on dor...
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ABSTRACT
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Rationale The α4β2 nicotinic acetylcholine receptors (α4β2-nAChRs) may represent useful targets for cognitive improvement. It has been recently proposed that a strategy based on positive allosteric modulation of α4β2-nAChRs reveals... more
Rationale The α4β2 nicotinic acetylcholine receptors (α4β2-nAChRs) may represent useful targets for cognitive improvement. It has been recently proposed that a strategy based on positive allosteric modulation of α4β2-nAChRs reveals several advantages over the direct agonist approach. Nevertheless, the procognitive effects of α4β2-nAChR positive allosteric modulators (PAMs) have not been extensively characterized. Objectives The aim of the present study was to evaluate the procognitive efficacy of desformylflustrabromine (dFBr), a selective α4β2-nAChR PAM. Methods Cognitive effects were investigated in the novel object recognition task (NORT) and the attentional set-shifting task (ASST) in rats. Results The results demonstrate that dFBr attenuated the delay-induced impairment in NORT performance and facilitated cognitive flexibility in the ASST. The beneficial effects of dFBr were inhibited by dihydro-β-erythroidine, a relatively selective α4β2-nAChR antagonist, indicating the involv...
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... nicotinic acetylcholine receptors Hugo R. Arias Department of Pharmaceutical Sciences, College of Pharmacy, Midwestern University, Glendale, AZ 85308, USA Tel.: +1 623 572 3589; Fax: +1 623 572 3550; E-mail: harias@midwestern.edu ...... more
... nicotinic acetylcholine receptors Hugo R. Arias Department of Pharmaceutical Sciences, College of Pharmacy, Midwestern University, Glendale, AZ 85308, USA Tel.: +1 623 572 3589; Fax: +1 623 572 3550; E-mail: harias@midwestern.edu ... Carroll et al. [29] hα3β4* BP 1.8 ± 0.2 ...
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... EndostatinTM Phase II Inhibits α5β1and αvβ3 integrins Breast cancer Mecamylamine Phase II Unspecific AChR noncompetitive antagonist Age-related macular degeneration and dia-betic macular edema Veglin Phase II Antisense-VEGF... more
... EndostatinTM Phase II Inhibits α5β1and αvβ3 integrins Breast cancer Mecamylamine Phase II Unspecific AChR noncompetitive antagonist Age-related macular degeneration and dia-betic macular edema Veglin Phase II Antisense-VEGF Mesothelioma ...
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Nicotinic acetylcholine receptors (AChRs) are the best characterized ion channels representing the Cys-loop receptor superfamily. AChRs have all the machinery to recognize the neurotransmitter ACh and other agonists such as nicotine, and... more
Nicotinic acetylcholine receptors (AChRs) are the best characterized ion channels representing the Cys-loop receptor superfamily. AChRs have all the machinery to recognize the neurotransmitter ACh and other agonists such as nicotine, and to transduce the agonist-induced conformational changes into the opening of the intrinsic cation channel. The gating machinery couples ligand binding, located at the extracellular portion, to the opening of the ion channel, located at the transmembrane region. The interface between the extracellular and the transmembrane domains is considered one of the most important structural and functional features for the process of gating. And finally, in the prolonged presence of agonists, the AChR becomes desensitized. Several drugs affect the functioning of these receptors. Among them, positive allosteric modulators (PAM) have acquired importance since are novel drugs for several neurological diseases. PAMs do not bind to the orthostetic binding sites but allosterically enhance the activity elicited by agonists by increasing the gating process and/or by decreasing desensitization. Instead, negative allosteric modulators (NAMs) produce the opposite effects. Interestingly, this negative effect is similar to that found for another class of allosteric drugs, i.e. non competitive antagonists (NCAs). However, the main difference between both categories of drugs is based on their distinct binding site locations. Although both NAMs and NCAs do not bind to the agonist sites, NACs bind to sites located in the ion channel, whereas NAMs bind to nonluminal sites. Interestingly, PAMs and NAMs might be developed as potential medications for the treatment of several diseases involving AChRs including, dementia-, skin-, and immunological-related diseases, drug addiction, and cancer. More exciting is the potential combination of specific agonists with PAMs. However, we are still in the beginning of understanding how these compounds act and how these drugs can be used therapeutically.
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The nicotinic acetylcholine receptor (AChR) is the archetype of the Cys-loop ligand-gated ion channel receptor superfamily. Noncompetitive antagonists inhibit the AChR without interacting directly with agonist sites. Among noncompetitive... more
The nicotinic acetylcholine receptor (AChR) is the archetype of the Cys-loop ligand-gated ion channel receptor superfamily. Noncompetitive antagonists inhibit the AChR without interacting directly with agonist sites. Among noncompetitive antagonists, general and local anesthetics have been used for decades to study the structure and function of muscle- as well as neuronal-type AChRs. In this review, we address and update all information regarding the characterization of binding sites and the mechanism of action for n-alkanols, barbiturates, inhalational and dissociative general anesthetics, as well as for tertiary and quaternary local anesthetics. The experimental evidence outlined in this review suggest that: (1) several neuronal-type AChRs might be targets for the pharmacological action of distinct anesthetics; (2) the molecular components of a specific anesthetic locus on a certain receptor type are different from the structural determinants of the site for the same anesthetic on a different receptor type; (3) there are unique binding sites for distinct anesthetics in the same receptor; (4) the affinity of a specific anesthetic depends on the AChR conformational state; (5) anesthetics may inhibit AChRs by different mechanisms including open-channel-blocking, augmenting the desensitization process, and/or inactivating the opening of resting receptors; and (6) some anesthetics may potentiate AChR activity.
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Nicotine is the main psychoactive substance present in tobacco, targeting neuronal nicotinic acetylcholine receptors (AChRs). The main effects of nicotine associated with smoking are AChR activation, desensitization, and upregulation,... more
Nicotine is the main psychoactive substance present in tobacco, targeting neuronal nicotinic acetylcholine receptors (AChRs). The main effects of nicotine associated with smoking are AChR activation, desensitization, and upregulation, with the subsequent modulation of the ...
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Dysfunction in alpha7 nicotinic acetylcholine receptor (nAChR), a member of the Cys-loop ligand-gated ion channel superfamily, is responsible for attentional and cognitive deficits in... more
Dysfunction in alpha7 nicotinic acetylcholine receptor (nAChR), a member of the Cys-loop ligand-gated ion channel superfamily, is responsible for attentional and cognitive deficits in Alzheimer's disease (AD). To provide useful information for finding drug candidates for the treatment of AD, a study was carried out according to the following procedures. (1) DMXBA, a partial agonist of the alpha7 nAChR, was used as a template molecule. (2) To reduce the number of compounds to be considered, the similarity search and flexible alignment were conducted to exclude those molecules which did not match the template. (3) The molecules thus obtained were docked to alpha7 nAChR. (4) To gain more structural information, the molecular dynamics (MD) simulations were carried out for 9 most favorable agonists obtained by the aforementioned docking studies. (5) By analyzing the hydrogen bond interaction and hydrophobic/hydrophilic interaction, the following seven compounds were singled out as possible drug candidates for AD therapy: gx-50, gx-51, gx-52, gx-180, open3d-99008, open3d-51265, open3d-60247.