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Fernando B De Moura - One of the best experts on this subject based on the ideXlab platform.
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unexpected loss of sensitivity to the nicotinic acetylcholine receptor antagonist activity of mecamylamine and dihydro β erythroidine in nicotine tolerant mice
Brain and behavior, 2020Co-Authors: Fernando B De Moura, Jenny L Wilkerson, Lance R McmahonAbstract:OBJECTIVES There is a long-standing interest in developing nicotinic acetylcholine receptor (nAChR) antagonists for concomitant use with nAChR agonists (e.g., nicotine replacement) as complementary smoking cessation aids. Previous studies demonstrate that daily nicotine treatment confers tolerance to some effects of nicotine, as well as cross-tolerance to other nAChR agonists. The current study assessed the extent to which antagonism of nicotine varies as a function of daily nicotine treatment. METHODS Schedule-controlled responding and hypothermia were selected for study because they have been previously used to examine the pharmacology of nicotine, and both are sensitive to the development nicotine tolerance. The rate-decreasing and hypothermic effects of nicotine, as well as antagonism of those effects, were examined in C57BL/6J mice before, during treatment with, and after discontinuation of three daily injections of 1.78 mg/kg nicotine. The nonselective nAChR antagonist mecamylamine and the β2 nAChR antagonist dihydro-β-erythroidine (DHβE) were studied in combination with nicotine. RESULTS The ED50 values of nicotine to produce rate-decreasing and hypothermic effects were, respectively, 0.44 and 0.82 mg/kg prior, 1.6 and 3.2 mg/kg during, and 0.74 and 1.1 mg/kg after discontinuation of daily nicotine treatment. Prior to daily nicotine treatment, mecamylamine decreased response rate and rectal temperature. However, during daily nicotine, mecamylamine (up to 5.6 mg/kg) only decreased rectal temperature. DHβE (up to 5.6 mg/kg) when studied prior to daily nicotine decreased rectal temperature, but that decrease was abolished during chronic nicotine treatment. Mecamylamine and DHβE antagonized the rate-decreasing and hypothermic effects of nicotine before and after daily nicotine; however, during daily nicotine, mecamylamine and DHβE antagonized only the hypothermic effects of nicotine. CONCLUSIONS The differential antagonism of rate-decreasing and hypothermic effects implicates differential involvement of nAChR subtypes. The decreased capacity of mecamylamine and DHβE to antagonize nicotine during chronic nicotine treatment may indicate that their effectiveness as smoking cessations might vary as a function of nicotine tolerance and dependence.
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unexpected loss of sensitivity to the nicotinic acetylcholine receptor antagonist activity of mecamylamine and dihydro β erythroidine in nicotine tolerant mice
Brain and behavior, 2020Co-Authors: Fernando B De Moura, Jenny L Wilkerson, Lance R McmahonAbstract:OBJECTIVES: There is a long-standing interest in developing nicotinic acetylcholine receptor (nAChR) antagonists for concomitant use with nAChR agonists (e.g., nicotine replacement) as complementary smoking cessation aids. Previous studies demonstrate that daily nicotine treatment confers tolerance to some effects of nicotine, as well as cross-tolerance to other nAChR agonists. The current study assessed the extent to which antagonism of nicotine varies as a function of daily nicotine treatment. METHODS: Schedule-controlled responding and hypothermia were selected for study because they have been previously used to examine the pharmacology of nicotine, and both are sensitive to the development nicotine tolerance. The rate-decreasing and hypothermic effects of nicotine, as well as antagonism of those effects, were examined in C57BL/6J mice before, during treatment with, and after discontinuation of three daily injections of 1.78 mg/kg nicotine. The nonselective nAChR antagonist mecamylamine and the beta2 nAChR antagonist dihydro-beta-erythroidine (DHbetaE) were studied in combination with nicotine. RESULTS: The ED50 values of nicotine to produce rate-decreasing and hypothermic effects were, respectively, 0.44 and 0.82 mg/kg prior, 1.6 and 3.2 mg/kg during, and 0.74 and 1.1 mg/kg after discontinuation of daily nicotine treatment. Prior to daily nicotine treatment, mecamylamine decreased response rate and rectal temperature. However, during daily nicotine, mecamylamine (up to 5.6 mg/kg) only decreased rectal temperature. DHbetaE (up to 5.6 mg/kg) when studied prior to daily nicotine decreased rectal temperature, but that decrease was abolished during chronic nicotine treatment. Mecamylamine and DHbetaE antagonized the rate-decreasing and hypothermic effects of nicotine before and after daily nicotine; however, during daily nicotine, mecamylamine and DHbetaE antagonized only the hypothermic effects of nicotine. CONCLUSIONS: The differential antagonism of rate-decreasing and hypothermic effects implicates differential involvement of nAChR subtypes. The decreased capacity of mecamylamine and DHbetaE to antagonize nicotine during chronic nicotine treatment may indicate that their effectiveness as smoking cessations might vary as a function of nicotine tolerance and dependence.
Lance R Mcmahon - One of the best experts on this subject based on the ideXlab platform.
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unexpected loss of sensitivity to the nicotinic acetylcholine receptor antagonist activity of mecamylamine and dihydro β erythroidine in nicotine tolerant mice
Brain and behavior, 2020Co-Authors: Fernando B De Moura, Jenny L Wilkerson, Lance R McmahonAbstract:OBJECTIVES There is a long-standing interest in developing nicotinic acetylcholine receptor (nAChR) antagonists for concomitant use with nAChR agonists (e.g., nicotine replacement) as complementary smoking cessation aids. Previous studies demonstrate that daily nicotine treatment confers tolerance to some effects of nicotine, as well as cross-tolerance to other nAChR agonists. The current study assessed the extent to which antagonism of nicotine varies as a function of daily nicotine treatment. METHODS Schedule-controlled responding and hypothermia were selected for study because they have been previously used to examine the pharmacology of nicotine, and both are sensitive to the development nicotine tolerance. The rate-decreasing and hypothermic effects of nicotine, as well as antagonism of those effects, were examined in C57BL/6J mice before, during treatment with, and after discontinuation of three daily injections of 1.78 mg/kg nicotine. The nonselective nAChR antagonist mecamylamine and the β2 nAChR antagonist dihydro-β-erythroidine (DHβE) were studied in combination with nicotine. RESULTS The ED50 values of nicotine to produce rate-decreasing and hypothermic effects were, respectively, 0.44 and 0.82 mg/kg prior, 1.6 and 3.2 mg/kg during, and 0.74 and 1.1 mg/kg after discontinuation of daily nicotine treatment. Prior to daily nicotine treatment, mecamylamine decreased response rate and rectal temperature. However, during daily nicotine, mecamylamine (up to 5.6 mg/kg) only decreased rectal temperature. DHβE (up to 5.6 mg/kg) when studied prior to daily nicotine decreased rectal temperature, but that decrease was abolished during chronic nicotine treatment. Mecamylamine and DHβE antagonized the rate-decreasing and hypothermic effects of nicotine before and after daily nicotine; however, during daily nicotine, mecamylamine and DHβE antagonized only the hypothermic effects of nicotine. CONCLUSIONS The differential antagonism of rate-decreasing and hypothermic effects implicates differential involvement of nAChR subtypes. The decreased capacity of mecamylamine and DHβE to antagonize nicotine during chronic nicotine treatment may indicate that their effectiveness as smoking cessations might vary as a function of nicotine tolerance and dependence.
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unexpected loss of sensitivity to the nicotinic acetylcholine receptor antagonist activity of mecamylamine and dihydro β erythroidine in nicotine tolerant mice
Brain and behavior, 2020Co-Authors: Fernando B De Moura, Jenny L Wilkerson, Lance R McmahonAbstract:OBJECTIVES: There is a long-standing interest in developing nicotinic acetylcholine receptor (nAChR) antagonists for concomitant use with nAChR agonists (e.g., nicotine replacement) as complementary smoking cessation aids. Previous studies demonstrate that daily nicotine treatment confers tolerance to some effects of nicotine, as well as cross-tolerance to other nAChR agonists. The current study assessed the extent to which antagonism of nicotine varies as a function of daily nicotine treatment. METHODS: Schedule-controlled responding and hypothermia were selected for study because they have been previously used to examine the pharmacology of nicotine, and both are sensitive to the development nicotine tolerance. The rate-decreasing and hypothermic effects of nicotine, as well as antagonism of those effects, were examined in C57BL/6J mice before, during treatment with, and after discontinuation of three daily injections of 1.78 mg/kg nicotine. The nonselective nAChR antagonist mecamylamine and the beta2 nAChR antagonist dihydro-beta-erythroidine (DHbetaE) were studied in combination with nicotine. RESULTS: The ED50 values of nicotine to produce rate-decreasing and hypothermic effects were, respectively, 0.44 and 0.82 mg/kg prior, 1.6 and 3.2 mg/kg during, and 0.74 and 1.1 mg/kg after discontinuation of daily nicotine treatment. Prior to daily nicotine treatment, mecamylamine decreased response rate and rectal temperature. However, during daily nicotine, mecamylamine (up to 5.6 mg/kg) only decreased rectal temperature. DHbetaE (up to 5.6 mg/kg) when studied prior to daily nicotine decreased rectal temperature, but that decrease was abolished during chronic nicotine treatment. Mecamylamine and DHbetaE antagonized the rate-decreasing and hypothermic effects of nicotine before and after daily nicotine; however, during daily nicotine, mecamylamine and DHbetaE antagonized only the hypothermic effects of nicotine. CONCLUSIONS: The differential antagonism of rate-decreasing and hypothermic effects implicates differential involvement of nAChR subtypes. The decreased capacity of mecamylamine and DHbetaE to antagonize nicotine during chronic nicotine treatment may indicate that their effectiveness as smoking cessations might vary as a function of nicotine tolerance and dependence.
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unexpected loss of sensitivity to the nachr antagonist activity of mecamylamine and dhβe in nicotine tolerant c57bl 6j mice
bioRxiv, 2018Co-Authors: Lance R McmahonAbstract:There has always been interest in developing nAChR antagonists as smoking cessation aids, to add to nAChR agonists (e.g., nicotine replacement) already used for that indication. Previous studies have demonstrated that daily nicotine treatment confers tolerance to some of the effects of nicotine, as well as cross-tolerance to other nAChR agonists. The current study assessed the extent to which antagonism of nicotine varies as a function of daily nicotine treatment. The rate-decreasing and hypothermic effects of nicotine, as well as antagonism of those effects, were examined in C57BL/6J mice before, during treatment with, and after discontinuation of three daily injections of 1.78 mg/kg nicotine. The nonselective nAChR antagonist mecamylamine and the β2 nAChR antagonist DHβE were studied in combination with nicotine. The ED50 values of nicotine to produce rate-decreasing and hypothermic effects were, respectively, 0.44 and 0.82 mg/kg prior, 1.6 and 3.2 mg/kg during, and 0.74 and 1.1 mg/kg after discontinuation of daily nicotine treatment. Prior to daily nicotine treatment, mecamylamine decreased response rate and rectal temperature; however, during daily nicotine, mecamylamine (up to 5.6 mg/kg) only decreased rectal temperature. DHβE (up to 5.6 mg/kg) when studied prior to daily nicotine decreased rectal temperature, but that decrease was abolished during chronic nicotine treatment. Mecamylamine and DHβE antagonized the rate-decreasing and hypothermic effects of nicotine before and after daily nicotine; however, during daily nicotine, mecamylamine and DHβE antagonized only the hypothermic effects of nicotine. The differential antagonism of rate-decreasing and hypothermic effects implicates differential involvement of nAChR subtypes. The decreased capacity of mecamylamine and DHβE to antagonize nicotine during chronic nicotine treatment may indicate that their effectiveness as smoking cessations might vary as a function of nicotine tolerance and dependence.
Neal L. Benowitz - One of the best experts on this subject based on the ideXlab platform.
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nicotine reduction strategy state of the science and challenges to tobacco control policy and fda tobacco product regulation
Preventive Medicine, 2018Co-Authors: Neal L. Benowitz, Jack E HenningfieldAbstract:Abstract Nicotine addiction is the proximate cause of disease and death from cigarette smoking. In 1994, we proposed reducing the nicotine content of cigarettes to non-addicting levels to reduce the risk of youth becoming addicted smokers and promoting quitting in established smokers. In 2009, the Family Smoking Prevention and Tobacco Control Act provided the authority to FDA to reduce nicotine levels as appropriate to benefit public health. Over the past 15 years, considerable research has determined that nicotine reduction is feasible and safe, resulting in reduced nicotine dependence with little evidence of compensatory over-smoking. The availability of acceptable non-combusted form of nicotine would provide support and enhance acceptability of nicotine reduction in tobacco. Most recently, the FDA promulgated a nicotine-based regulatory framework, which includes nicotine reduction combined with ready availability of noncombustible nicotine products. Nicotine reduction could contribute to a virtual end to the use of cigarette smoking, with enormous benefits to public health.
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cessation of alcohol consumption decreases rate of nicotine metabolism in male alcohol dependent smokers
Drug and Alcohol Dependence, 2016Co-Authors: Noah R Gubner, Neal L. Benowitz, Peyton Jacob, Aleksandra Kozarkonieczna, Izabela Szoltysekboldys, Ewa Slodczykmankowska, Jerzy Goniewicz, Andrzej Sobczak, Maciej L GoniewiczAbstract:Abstract Background Rate of nicotine metabolism is an important factor influencing cigarette smoking behavior, dependence, and efficacy of nicotine replacement therapy. The current study examined the hypothesis that chronic alcohol abuse can accelerate the rate of nicotine metabolism. Nicotine metabolite ratio (NMR, a biomarker for rate of nicotine metabolism) and patterns of nicotine metabolites were assessed at three time points after alcohol cessation. Methods Participants were 22 Caucasian men randomly selected from a sample of 165 smokers entering a 7-week alcohol dependence treatment program in Poland. Data were collected at three time points: baseline (week 1, after acute alcohol detoxification), week 4, and week 7. Urine was analyzed for nicotine and metabolites and used to determine the nicotine metabolite ratio (NMR, a biomarker for rate of nicotine metabolism), and total nicotine equivalents (TNE, a biomarker for total daily nicotine exposure). Results and conclusions There was a significant decrease in urine NMR over the 7 weeks after alcohol abstinence (F(2,42) = 18.83, p
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arteriovenous differences in plasma concentration of nicotine and catecholamines and related cardiovascular effects after smoking nicotine nasal spray and intravenous nicotine
Clinical Pharmacology & Therapeutics, 1997Co-Authors: Steven G Gourlay, Neal L. BenowitzAbstract:Background and objectives Delivery of a high concentration bolus of nicotine through the arterial circulation is believed to be an important determinant of the addictive, behavioral, and physiologic effects of nicotine. To better understand the pharmacologic features of nicotine with different routes of administration, we measured arterial and venous plasma concentrations of nicotine, cotinine, epinephrine, and norepinephrine after tobacco smoking, intravenous nicotine infusion, and use of a nicotine nasal spray. Subjects and methods Arterial and venous blood samples were drawn simultaneously from 12 male smokers. Six subjects received a single dose of 1 mg nicotine nasal spray, and six subjects smoked cigarettes, one puff per minute for 10 minutes. All 12 subjects were administered nicotine as a 30-minute infusion beginning 70 minutes after administration of the nicotine nasal spray or commencement of smoking. Results The mean peak arterial plasma concentrations of nicotine (Cmax) after smoking or administration of nicotine nasal spray, or intravenous nicotine averaged twofold those of venous plasma. For nicotine nasal spray, the time to Cmax was much faster for arterial than for venous plasma (median, 5 versus 18 minutes, p < 0.01). Intravenous nicotine produced the greatest increase in plasma epinephrine concentration, although smoking had a greater chronotropic effect. Acute tolerance to the chronotropic effects of nicotine was suggested at pharmacodynamic analysis with venous nicotine concentrations, whereas analysis of arterial concentrations found the opposite—a time lag between plasma concentration and effect. Conclusion Nicotine is rapidly absorbed from nicotine nasal spray. The Cmax of nicotine after smoking or administration of nicotine nasal spray, or intravenous nicotine is substantially higher in arterial than venous plasma. Acute tolerance to the chronotropic effects of nicotine is not apparent if arterial plasma concentrations are measured. Clinical Pharmacology & Therapeutics (1997) 62, 453–463; doi:
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sources of variability in nicotine and cotinine levels with use of nicotine nasal spray transdermal nicotine and cigarette smoking
British Journal of Clinical Pharmacology, 1997Co-Authors: Neal L. Benowitz, Shoshana Zevin, Peyton JacobAbstract:Author(s): Benowitz, NL; Zevin, S; Jacob, P | Abstract: AIMS:Nicotine nasal spray and transdermal nicotine are effective aids to smoking cessation, and are being evaluated for treatment of other medical diseases. Wide variation in levels of nicotine and its metabolite, cotinine, have been observed with such therapies. This study aimed primarily to assess sources of individual variability in nicotine and metabolite plasma levels from these dosing systems and from cigarette smoking. METHODS:Twelve cigarette smokers, studied on a clinical research ward, received four treatments of 5 days duration each, including (1) cigarette smoking, 16 cigarettes/day; (2) transdermal nicotine, 15 mg/day; (3) nicotine nasal spray, 24-1 mg doses/day; (4) placebo nicotine nasal spray, 24 doses/day. On a different occasion, the disposition kinetics of nicotine and cotinine were determined via infusion of deuterium-labeled nicotine and continine. Plasma levels of nicotine, cotinine, and 3'-hydroxycotinine and daily intake of nicotine during various treatments were examined, as well as pharmacokinetic factors that determined plasma nicotine and continine levels. RESULTS:There was considerable individual variation in plasma nicotine and cotinine levels and in the daily of nicotine absorbed from various delivery systems, with most variability with nicotine nasal spray (fivefold) and least for transdermal nicotine (two-to threefold). Plasma nicotine levels were determined most strongly by nicotine clearance. Continine levels were determined most strongly by dose of nicotine and, to a lesser extent, the clearance of cotinine and fractional conversion of nicotine to continine. CONCLUSIONS:Plasma levels of nicotine and cotinine produced by nicotine therapies are highly variable, due to both wide variability in individual pharmacokinetics and in dose delivery from the products. To compensate for individual differences in clearance, individualization of nicotine dosing based on therapeutic drug monitoring with comparison to nicotine or continine levels during cigarette smoking prior to treatment may be necessary to optimize nicotine therapy. This study also validates a recently proposed method for estimating absolute bioavailability of a drug using drug and metabolite pharmacokinetic data, and presents novel data on plasma levels of the metabolite trans-3'-hydroxycotinine in people.
Peyton Jacob - One of the best experts on this subject based on the ideXlab platform.
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cessation of alcohol consumption decreases rate of nicotine metabolism in male alcohol dependent smokers
Drug and Alcohol Dependence, 2016Co-Authors: Noah R Gubner, Neal L. Benowitz, Peyton Jacob, Aleksandra Kozarkonieczna, Izabela Szoltysekboldys, Ewa Slodczykmankowska, Jerzy Goniewicz, Andrzej Sobczak, Maciej L GoniewiczAbstract:Abstract Background Rate of nicotine metabolism is an important factor influencing cigarette smoking behavior, dependence, and efficacy of nicotine replacement therapy. The current study examined the hypothesis that chronic alcohol abuse can accelerate the rate of nicotine metabolism. Nicotine metabolite ratio (NMR, a biomarker for rate of nicotine metabolism) and patterns of nicotine metabolites were assessed at three time points after alcohol cessation. Methods Participants were 22 Caucasian men randomly selected from a sample of 165 smokers entering a 7-week alcohol dependence treatment program in Poland. Data were collected at three time points: baseline (week 1, after acute alcohol detoxification), week 4, and week 7. Urine was analyzed for nicotine and metabolites and used to determine the nicotine metabolite ratio (NMR, a biomarker for rate of nicotine metabolism), and total nicotine equivalents (TNE, a biomarker for total daily nicotine exposure). Results and conclusions There was a significant decrease in urine NMR over the 7 weeks after alcohol abstinence (F(2,42) = 18.83, p
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sources of variability in nicotine and cotinine levels with use of nicotine nasal spray transdermal nicotine and cigarette smoking
British Journal of Clinical Pharmacology, 1997Co-Authors: Neal L. Benowitz, Shoshana Zevin, Peyton JacobAbstract:Author(s): Benowitz, NL; Zevin, S; Jacob, P | Abstract: AIMS:Nicotine nasal spray and transdermal nicotine are effective aids to smoking cessation, and are being evaluated for treatment of other medical diseases. Wide variation in levels of nicotine and its metabolite, cotinine, have been observed with such therapies. This study aimed primarily to assess sources of individual variability in nicotine and metabolite plasma levels from these dosing systems and from cigarette smoking. METHODS:Twelve cigarette smokers, studied on a clinical research ward, received four treatments of 5 days duration each, including (1) cigarette smoking, 16 cigarettes/day; (2) transdermal nicotine, 15 mg/day; (3) nicotine nasal spray, 24-1 mg doses/day; (4) placebo nicotine nasal spray, 24 doses/day. On a different occasion, the disposition kinetics of nicotine and cotinine were determined via infusion of deuterium-labeled nicotine and continine. Plasma levels of nicotine, cotinine, and 3'-hydroxycotinine and daily intake of nicotine during various treatments were examined, as well as pharmacokinetic factors that determined plasma nicotine and continine levels. RESULTS:There was considerable individual variation in plasma nicotine and cotinine levels and in the daily of nicotine absorbed from various delivery systems, with most variability with nicotine nasal spray (fivefold) and least for transdermal nicotine (two-to threefold). Plasma nicotine levels were determined most strongly by nicotine clearance. Continine levels were determined most strongly by dose of nicotine and, to a lesser extent, the clearance of cotinine and fractional conversion of nicotine to continine. CONCLUSIONS:Plasma levels of nicotine and cotinine produced by nicotine therapies are highly variable, due to both wide variability in individual pharmacokinetics and in dose delivery from the products. To compensate for individual differences in clearance, individualization of nicotine dosing based on therapeutic drug monitoring with comparison to nicotine or continine levels during cigarette smoking prior to treatment may be necessary to optimize nicotine therapy. This study also validates a recently proposed method for estimating absolute bioavailability of a drug using drug and metabolite pharmacokinetic data, and presents novel data on plasma levels of the metabolite trans-3'-hydroxycotinine in people.
Becerra Cruz, Gina Paola - One of the best experts on this subject based on the ideXlab platform.
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Caracterización molecular de una serie de análogos de nicotina y su interacción con receptores nicotínicos α7
Maestría en Ciencias Biológicas, 2018Co-Authors: Becerra Cruz, Gina PaolaAbstract:Diversos trabajos que caracterizan la nicotina se han llevado a cabo desde aproximaciones experimentales y teóricas; contrariamente para análogos solo se ha desarrollado un estudio conformacional para selenoanálogos. Esto motivó realizar la caracterización molecular de una serie de ocho análogos de nicotina. Nótese que, aunque para algunos de estos análogos ya hay reportes de su afinidad por receptores nicotínicos, los mecanismos no se conocen aún muy bien por tanto este tipo de estudios proveen datos geométricos, energéticos, poblacionales, entre otros, que permiten explicar dichos mecanismos. Para el desarrollo de este trabajo fueron empleados los siguientes programas: Avogadro para el diseño 3D y la obtención de confórmeros; Gaussian09 en la optimización geométrica de los confórmeros usando cálculos DFT (B3LYP y la base aug-cc-pVDZ), NBO para los cálculos de población electrónica y AIMAllProfessional para el análisis topológico de la densidad electrónica. Se obtuvieron 24 geometrías estables a partir de los cálculos de optimización y frecuencias de 114 confórmeros: A1(2), A2(2), A3(2), A4(2), A5(6), A6(6), A7(2) y A8(2), AX(Y)=A: análogo, X=1 a 8, y: número de estructuras estables. La caracterización molecular se ha centrado en datos geométricos como distancias de las interacciones intramoleculares, cargas atómicas de los átomos involucrados en dichas interacciones, así como la densidad electrónica en los puntos críticos de enlace hallando en algunos casos correlaciones interesantes entre dichos parámetros.Several works that characterize nicotine have been developed from experimental (1) and/or theoretical (2) point of view; contrary, according to our best knowledge, for nicotine analogs, these is few reports such a conformational study for selenoanalogs (3). This motivates us to perform computationally molecular characterization of a serie of eight nicotine analogs whit pyrrolidine ring modifications. Note that although for some these analogs there are reports about their nicotine receptors affinity (4); the mechanisms are unknown yet. Therefore, this study provides geometry, energy, population data, among others, which could help to explain these mechanisms. For development of this work the following programs were employed: Avogadro for 3D design and conformer search; DFT (B3LYP/aug-cc-pVDZ) calculations with Gaussian 09 for conformers geometry optimization; NBO for electronic population calculations and AIMAllProfessional topological analysis of the electronic density. We report 24 stable geometries from optimization calculations and frequencies of 144 conformational structures: A1(2), A2(2), A3(2), A4(2), A5(6), A6(6), A7(2) y A8(2); AX(Y)= A: analog, X=1 to 8, Y: number of stable structures. The molecular characterization has focused in geometries data as intermolecular interactions distances, atomic charges of atoms involved in such interactions, as well as electronic density in bond critical points, in some cases interesting correlations among such parameters have been found
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Caracterización molecular de una serie de análogos de nicotina y su interacción con receptores nicotínicos α7
'Universidad Nacional Hermilio Valdizan - Facultad de Ciencias de la Educacion', 2018Co-Authors: Becerra Cruz, Gina PaolaAbstract:Diversos trabajos que caracterizan la nicotina se han llevado a cabo desde aproximaciones experimentales y teóricas; contrariamente para análogos solo se ha desarrollado un estudio conformacional para selenoanálogos. Esto motivó realizar la caracterización molecular de una serie de ocho análogos de nicotina. Nótese que, aunque para algunos de estos análogos ya hay reportes de su afinidad por receptores nicotínicos, los mecanismos no se conocen aún muy bien por tanto este tipo de estudios proveen datos geométricos, energéticos, poblacionales, entre otros, que permiten explicar dichos mecanismos. Para el desarrollo de este trabajo fueron empleados los siguientes programas: Avogadro para el diseño 3D y la obtención de confórmeros; Gaussian09 en la optimización geométrica de los confórmeros usando cálculos DFT (B3LYP y la base aug-cc-pVDZ), NBO para los cálculos de población electrónica y AIMAllProfessional para el análisis topológico de la densidad electrónica. Se obtuvieron 24 geometrías estables a partir de los cálculos de optimización y frecuencias de 114 confórmeros: A1(2), A2(2), A3(2), A4(2), A5(6), A6(6), A7(2) y A8(2), AX(Y)=A: análogo, X=1 a 8, y: número de estructuras estables. La caracterización molecular se ha centrado en datos geométricos como distancias de las interacciones intramoleculares, cargas atómicas de los átomos involucrados en dichas interacciones, así como la densidad electrónica en los puntos críticos de enlace hallando en algunos casos correlaciones interesantes entre dichos parámetros.Several works that characterize nicotine have been developed from experimental (1) and/or theoretical (2) point of view; contrary, according to our best knowledge, for nicotine analogs, these is few reports such a conformational study for selenoanalogs (3). This motivates us to perform computationally molecular characterization of a serie of eight nicotine analogs whit pyrrolidine ring modifications. Note that although for some these analogs there are reports about their nicotine receptors affinity (4); the mechanisms are unknown yet. Therefore, this study provides geometry, energy, population data, among others, which could help to explain these mechanisms. For development of this work the following programs were employed: Avogadro for 3D design and conformer search; DFT (B3LYP/aug-cc-pVDZ) calculations with Gaussian 09 for conformers geometry optimization; NBO for electronic population calculations and AIMAllProfessional topological analysis of the electronic density. We report 24 stable geometries from optimization calculations and frequencies of 144 conformational structures: A1(2), A2(2), A3(2), A4(2), A5(6), A6(6), A7(2) y A8(2); AX(Y)= A: analog, X=1 to 8, Y: number of stable structures. The molecular characterization has focused in geometries data as intermolecular interactions distances, atomic charges of atoms involved in such interactions, as well as electronic density in bond critical points, in some cases interesting correlations among such parameters have been found.Magíster en Ciencias BiológicasMaestrí
