No abstract available.
Receptors, Nicotinic*

Three dimensional quantitative structure activity relationship between diazabicyclo[4.2.0]octanes and nicotinic acetylcholine receptor (h alpha4beta2 and h alpha3beta4) agonists was studied using comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA). From 11 CoMFA and CoMSIA models, CoMSIA with steric and electrostatic fields gave the best predictive models (q2=0.926 and 0.945, r2(ncv)=0.983 and 0.988). This study can be used to develop potent h alpha4beta2 receptor agonists with low activity on h alpha3beta4 subtype.
Quantitative Structure-Activity Relationship ; Receptors, Nicotinic

Nicotinic acid could increase high density lipoprotein and reduce serum total cholesterol, low density lipoprotein cholesterol and triglycerides in human bodies, thus is frequently applied in treating low high-density lipoprotein cholesterol and hypertriglyceridemia in clinic. However, according to the findings, nicotinic acid could also cause adverse effects, such as skin flush, beside its curative effects. In this study, bioisosterism, fragment-based search and Lipinski's Rule of Five were used to preliminarily screen out potential TCM ingredients that may have similar pharmacological effects with nicotinic acid from Traditional Chinese medicine database (TCMD). Afterwards, homology modeling and flexible docking were used to further screen out potential nicotinic acid receptor agonists. As a result, eleven candidate compounds were derived from eight commonly used traditional Chinese medicines. Specifically, all of the candidate compounds' interaction with nicotinic acid receptor was similar to nicotinic acid, and their docking scores were all higher than that of nicotinic acid, but their druggability remained to be further studied. Some of the eight source traditional Chinese medicines were used to lower lipid according to literature studies, implying that they may show effect through above means. In summary, this study provides basis and reference for extracting new nicotinic acid receptor agonists from traditional Chinese medicines and improving the medication status of hyperlipidemia.
Drug Evaluation, Preclinical ; Drugs, Chinese Herbal ; chemistry ; Humans ; Models, Molecular ; Molecular Structure ; Nicotinic Acids ; chemistry ; Nicotinic Agonists ; chemistry ; Protein Binding ; Receptors, G-Protein-Coupled ; agonists ; chemistry ; Receptors, Nicotinic ; chemistry

The effects of presynaptic nicotinic acetylcholine receptors (nAChRs) on excitatory synaptic transmission in CA1 pyramidal neurons of the rat hippocampus were examined by blind whole-cell patch clamp recording from hippocampal slice preparations. Local application of the nAChRs agonist dimethylphenyl-piperazinium iodide (DMPP) did not induce a postsynaptic current response in CA1 pyramidal cells. However, DMPP enhanced the frequency and amplitude of spontaneous excitatory postsynaptic current (sEPSC) in these cells in a dose-dependent manner. This enhancement was blocked by the selective nicotinic alpha-7 receptor antagonist alpha-bungarotoxin, but not by the antagonist mecamylamine, hexamethonium or dihydro-beta-erythroidine. The frequency of miniature excitatory postsynaptic current (mEPSC) in CA1 pyramidal neurons was also increased by application of DMPP, indicating a presynaptic site of action of the agonist. Taken together, these results suggest that activation of presynaptic nAChRs in CA1 pyramidal neurons, which contain alpha-7 subunits, potentiates presynaptic glutamate release and consequently modulate excitatory synaptic transmission in the hippocampus.
Animals ; Bungarotoxins ; physiology ; Dimethylphenylpiperazinium Iodide ; pharmacology ; Glutamic Acid ; pharmacology ; Hippocampus ; physiology ; Male ; Neurons ; physiology ; Nicotinic Agonists ; pharmacology ; Pacemaker, Artificial ; Patch-Clamp Techniques ; Rats ; Rats, Wistar ; Receptors, Nicotinic ; physiology ; Receptors, Presynaptic ; physiology ; Synapses ; physiology ; Synaptic Transmission ; alpha7 Nicotinic Acetylcholine Receptor

PURPOSE: To identify the characteristics and physiological function of the nicotinic receptor expressed in human retinoblastoma cells. METHODS: We measured possible nicotinic signaling in WERI-Rb-1 cells using the Ca2+ imaging technique and the patch clamp method. RESULTS: 1) Nicotine-induced [Ca2+]i rise arose entirely through Ca2+ influx, which was completely abolished by hexamethonium (100 micro M). 2) Nicotine also induced remarkable depolarization from -56.6 +/- 3.7 mV to -29.6 +/- 3.6 mV (n=4) under current clamp mode, but it failed to directly activate the T-type Ca2+ channel expressed in retinoblastoma cells. CONCLUSIONS: Nicotinic activation can increase the intracellular calcium level through calcium influx in the undifferentiated retinoblastoma cells, which may play important roles in cell proliferation, differentiation, and cell death.
Calcium ; Cell Death ; Cell Proliferation ; Hexamethonium ; Humans* ; Nicotine ; Receptors, Nicotinic* ; Retinoblastoma*

The alpha9alpha10 nicotinic acetylcholine receptors (nAChRs) mediates efferent inhibition of hair cell function within the auditory sensory organ. Gating of the nAChRs leads to activation of calcium-dependent potassium channels to hyperpolarize the hair cell. In efferent system, main calcium providers to SK channel are nAChR and synaptic cistern, which contribution to efferent inhibition is different between avian and mammalian species. Calcium permeation is more effective in nAChRs of mammalian cochlea than avian cochlea, and mammalian calcium permeability of nAChRs is about 3 times more than avian hair cell. Thus, mammalian nAChRs is a main component of efferent inhibition in cochlear hair cell system.
Acetylcholine ; Calcium ; Cochlea ; Hair ; Permeability ; Potassium Channels, Calcium-Activated ; Receptors, Nicotinic

The alpha9alpha10 nicotinic acetylcholine receptors (nAChRs) mediates efferent inhibition of hair cell function within the auditory sensory organ. Gating of the nAChRs leads to activation of calcium-dependent potassium channels to hyperpolarize the hair cell. In efferent system, main calcium providers to SK channel are nAChR and synaptic cistern, which contribution to efferent inhibition is different between avian and mammalian species. Calcium permeation is more effective in nAChRs of mammalian cochlea than avian cochlea, and mammalian calcium permeability of nAChRs is about 3 times more than avian hair cell. Thus, mammalian nAChRs is a main component of efferent inhibition in cochlear hair cell system.
Acetylcholine ; Calcium ; Cochlea ; Hair ; Permeability ; Potassium Channels, Calcium-Activated ; Receptors, Nicotinic

BACKGROUND: Cholinesterase inhibitors (ChEIs) which have been widely used clinically are known to have diverse actions on the neuromuscular synaptic transmissions, suggesting that inhibiting cholinesterase (ChE) might not be their only mode of action. ChEIs interact with the nicotinic acetylcholine receptor (nAChR) macromolecule as a weak agonist, and as a modulator inducing desensitization and blockade at high concentrations. In a previous study, we reported that carbamate ChEIs, Pyridostigmine and Physostigmine could facilitate the ionic influx through nAChRs, when precluding the Ach-hydrolyzing effect of acetylChE (AChE) by applying carbachol as an agonist. The facilitation of the nAChR function was supposed to be achieved by AChE-mediated nAChR modulation and possibly by the up-regulation of nAChRs. METHODS: In this study, we analyzed the effect of irreversible organophosphate ChEI, diisopropylfluorophosphate (DFP) on the function of muscular nAChRs in TE671 cells, quantifying carbachol-induced intracellular 22 Na+ influx through nAChRs, using radioassay. RESULTS: Preincubation of cells with 1 mM DFP at 37 degrees C for 10 min as well as the simultaneous application of carbachol and DFP, decreased the carbachol-induced influx dose-dependently.However, preincubation of cells with 10 micrometer DFP potentiated the influx to 132.5+/-7.4% CPM. Moreover, Najar Tx completely inhibited the potentiated 22 Na + influx. CONCLUSIONS: Organophosphate ChEI can facilitate nAChR functions at low concentrations with a yet discovered mechanism, which is supposed to necessitate cellular metabolism, and be possibly mediated by AChE. The inhibition of DFP on nAChR functions at high concentration is attributable to its remained curare-like actions and direct cellular toxicity.
Carbachol ; Cholinesterase Inhibitors ; Cholinesterases* ; Isoflurophate ; Metabolism ; Physostigmine ; Pyridostigmine Bromide ; Receptors, Nicotinic* ; Up-Regulation

BACKGROUND: Varenicline, a selective partial agonist/antagonist of the alpha4beta2 nicotinic receptor, has proven effectiveness for smoking cessation by several randomized, controlled trials. Because few studies have evaluated the long-term efficacy of varenicline, we tried to evaluate the smoking status of varenicline users up to 3 years after the initial prescription of the drug. METHODS: We interviewed varenicline users who were prescribed the drug from June 2007 to May 2010 by telephone, from June 2010 to May 2011. RESULTS: One-hundred and thirty-three of 250 varenicline users (53.2%) were available for the survey. Seven-day continuous abstinence from smoking was adhered to by 17 of 39 respondents (43.6%) at 1 year, and 11 of 36 (30.6%) and 19 of 58 (32.8%) at 2 and 3 years since the first use of varenicline, respectively. Compared to current smokers, successful quitters were older (55.0 years vs. 49.9 years, p=0.01), had better compliance to the 12-week course (27.7 vs. 9.3%, p=0.01), and had taken varenicline longer (10.1 vs. 5.9 weeks, p=0.01). Fifty-four of 71 current smokers (76.1%) were willing to stop smoking in the near future. The preferred ways to cease smoking were will-power (48.1%), varenicline (25.9%), nicotine replacement therapy (11.1%), and others (14.9%). CONCLUSION: Smokers should be encouraged to stick to the proven way for recommended period of time for successful cessation of smoking.
Compliance ; Surveys and Questionnaires ; Nicotine ; Prescriptions ; Receptors, Nicotinic ; Smoke* ; Smoking Cessation ; Smoking* ; Telephone ; Varenicline

Quercetin is a flavonoid usually found in fruits and vegetables. Aside from its antioxidative effects, quercetin, like other flavonoids, has a various neuropharmacological actions. Quercetin-3-O-rhamnoside (Rham1), quercetin-3-O-rutinoside (Rutin), and quercetin-3-(2(G)-rhamnosylrutinoside (Rham2) are mono-, di-, and tri-glycosylated forms of quercetin, respectively. In a previous study, we showed that quercetin can enhance α7 nicotinic acetylcholine receptor (α7 nAChR)-mediated ion currents. However, the role of the carbohydrates attached to quercetin in the regulation of α7 nAChR channel activity has not been determined. In the present study, we investigated the effects of quercetin glycosides on the acetylcholine induced peak inward current (I(ACh)) in Xenopus oocytes expressing the α7 nAChR. I(ACh) was measured with a two-electrode voltage clamp technique. In oocytes injected with α7 nAChR copy RNA, quercetin enhanced I(ACh), whereas quercetin glycosides inhibited I(ACh). Quercetin glycosides mediated an inhibition of I(ACh), which increased when they were pre-applied and the inhibitory effects were concentration dependent. The order of I(ACh) inhibition by quercetin glycosides was Rutin≥Rham1>Rham2. Quercetin glycosides-mediated I(ACh) enhancement was not affected by ACh concentration and appeared voltage-independent. Furthermore, quercetin-mediated I(ACh) inhibition can be attenuated when quercetin is co-applied with Rham1 and Rutin, indicating that quercetin glycosides could interfere with quercetin-mediated α7 nAChR regulation and that the number of carbohydrates in the quercetin glycoside plays a key role in the interruption of quercetin action. These results show that quercetin and quercetin glycosides regulate the α7 nAChR in a differential manner.
Acetylcholine* ; Carbohydrates ; Flavonoids ; Fruit ; Glycosides* ; Humans* ; Oocytes ; Quercetin* ; Receptors, Nicotinic ; RNA ; Rutin ; Vegetables ; Xenopus