The configuration of nicotine. A nuclear magnetic resonance study

Whidby, Jerry F.; Seeman, Jeffrey I.

doi:10.1021/jo00871a022

Cited by 40 publications

(21 citation statements)

References 5 publications

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“…We can compare the calculated results with available experimental data to see how good the calculations are. Whidby and Seeman's NMR spectroscope studies 71 demonstrated that the protonated S-(−)-nicotine species with the methyl group trans to the pyridine ring predominates in solution to the extent of more than 90%. The latter observations indicate that the free energy of SRH should be lower than that of SSH by at least 1.37 kcal/mol, when T = 298.15 K. The experimentally-derived free energy difference of > 1.37 kcal/mol is in good agreement with our calculated free energy difference of 1.96 kcal/mol between SRH and SSH.…”

Section: Distribution Of the Molecular Species Of S-(−)-nicotine-thermentioning

confidence: 99%

Modeling Multiple Species of Nicotine and Deschloroepibatidine Interacting with α4β2 Nicotinic Acetylcholine Receptor: From Microscopic Binding to Phenomenological Binding Affinity

et al. 2005

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A variety of molecular modeling, molecular docking, and first-principles electronic structure calculations were performed to study how the alpha4beta2 nicotinic acetylcholine receptor (nAChR) binds with different species of two typical agonists, (S)-(-)-nicotine and (R)-(-)-deschloroepibatidine, each of which is distinguished by different free bases and protonation states. On the basis of these results, predictions were made regarding the corresponding microscopic binding free energies. Hydrogen-bonding and cation-pi interactions between the receptor and the respective ligands were found to be the dominant factors differentiating the binding strengths of different microscopic binding species. The calculated results and analyses demonstrate that, for each agonist, all the species are interchangeable and can quickly achieve a thermodynamic equilibrium in solution and at the nAChR binding site. This allows quantitation of the equilibrium concentration distributions of the free ligand species and the corresponding microscopic ligand-receptor binding species, their pH dependence, and their contributions to the phenomenological binding affinity. The predicted equilibrium concentration distributions, pK(a) values, absolute phenomenological binding affinities, and their pH dependence are all in good agreement with available experimental data, suggesting that the computational strategy from the microscopic binding species and affinities to the phenomenological binding affinity is reliable for studying alpha4beta2 nAChR-ligand binding. This should provide valuable information for future rational design of drugs targeting nAChRs. The general strategy of the "from-microscopic-to-phenomenological" approach for studying interactions of alpha4beta2 nAChRs with (S)-(-)-nicotine and (R)-(-)-deschloroepibatidine may also be useful in studying other types of ligand-protein interactions involving multiple molecular species of a ligand and in associated rational drug design.

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Section: Distribution Of the Molecular Species Of S-(−)-nicotine-thermentioning

confidence: 99%

Modeling Multiple Species of Nicotine and Deschloroepibatidine Interacting with α4β2 Nicotinic Acetylcholine Receptor: From Microscopic Binding to Phenomenological Binding Affinity

et al. 2005

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“…201 Moreover, recent studies utilizing nuclear magnetic resonance have shown that the preferred configuration of the N-methyl group in nicotine is trans to the pyridine ring. 202 Except for nicotine, no reports are available on the chirality of the optically active alkaloids as they are present in tobacco smoke. In the plant, however, anatabine and anabasine have been reported to occur both as the racemic mixture and in the / form.…”

Section: Pyridinesmentioning

confidence: 99%

Nitrogen-containing compounds in tobacco and tobacco smoke

Schmeltz¹,

Hoffmann²

1977

Chem. Rev.

322

154

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“…Crystal structures of both protonated [2] and diprotonated [3] nicotine show the trans form for the monoprotonated species exists in the solid phase. It was concluded from early NMR studies of protonated nicotine that the cis form predominates [4], while later studies at low pH on the diprotonated form found a 10:1 trans/cis ratio in solution [5]. Elmore and Dougherty have recently examined the relative energies of low energy conformations of nicotine, protonated nicotine, and diprotonated nicotine both in the gas phase and in water, using several computational methods [6].…”

Section: Introductionmentioning

confidence: 99%

Protonation-induced stereoisomerism in nicotine: Conformational studies using classical (AMBER) and ab initio (Car–Parrinello) molecular dynamics

Hammond¹,

Harris³

et al. 2005

J Comput Aided Mol Des

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A variety of biologically active small molecules contain prochiral tertiary amines, which become chiral centers upon protonation. S-nicotine, the prototypical nicotinic acetylcholine receptor agonist, produces two diastereomers on protonation. Results, using both classical (AMBER) and ab initio (Car-Parrinello) molecular dynamical studies, illustrate the significant differences in conformational space explored by each diastereomer. As is expected, this phenomenon has an appreciable effect on nicotine's energy hypersurface and leads to differentiation in molecular shape and divergent sampling. Thus, protonation induced isomerism can produce dynamic effects that may influence the behavior of a molecule in its interaction with a target protein. We also examine differences in the conformational dynamics for each diastereomer as quantified by both molecular dynamics methods.

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The configuration of nicotine. A nuclear magnetic resonance study

Cited by 40 publications

References 5 publications

Modeling Multiple Species of Nicotine and Deschloroepibatidine Interacting with α4β2 Nicotinic Acetylcholine Receptor: From Microscopic Binding to Phenomenological Binding Affinity

Modeling Multiple Species of Nicotine and Deschloroepibatidine Interacting with α4β2 Nicotinic Acetylcholine Receptor: From Microscopic Binding to Phenomenological Binding Affinity

Nitrogen-containing compounds in tobacco and tobacco smoke

Protonation-induced stereoisomerism in nicotine: Conformational studies using classical (AMBER) and ab initio (Car–Parrinello) molecular dynamics

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