Physicochemical properties of biological interest and structure of nicotine and its related compounds

Fujita, Toshio; Nakajima, Minoru; Soeda, Yoshinori; Yamamoto, Ichiro

doi:10.1016/0048-3575(71)90190-8

Cited by 23 publications

(16 citation statements)

References 12 publications

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“…Ample evidence exists that the monocationic form of nicotine and of most other ionizable nAChR agonists is the form that binds to nAChRs with highest affinity (Barlow and Hamilton, 1962;Jeng and Cohen, 1980;Kem et al, 2004). Since the published pK a for ionization of the 19-N of nicotine (8.05, Fujita et al, 1971) is 0.65 U above physiologic pH of 7.4, and the methylnicotine analogs were found to have similar pK a values (Supplemental Table 1), our pharmacological data in Tables 1-6 largely reflect the properties of the monocationic species and are uncorrected for the small differences in ionization we observed for the 19-ethyl-, 29-methyl-, and 59-methylnicotine analogs (see Supplemental Table 1 for estimation of the percentage of monocationic species for compounds expected to show the largest differences in ionization).…”

Section: Resultsmentioning

confidence: 99%

“…Ionization of the most basic N atom is essential for efficient binding of nicotine and most nicotinoids to various AChRs and AChBPs. The pyrrolidinyl N in nicotine has been reported to possess a pK a of 8.05 and a pyridyl ring N pK a of 3.85 (Fujita et al, 1971). Thus, at physiologic pH, there will be a mixture of the monocationic and unionized pyrrolidinyl forms, and their relative solution concentrations will depend upon the pH.…”

Section: Discussionmentioning

confidence: 99%

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A Methyl Scan of the Pyrrolidinium Ring of Nicotine Reveals Significant Differences in Its Interactions with α7 and α4β2 Nicotinic Acetylcholine Receptors

Xiao

Andrud

Soti

et al. 2020

Molecular Pharmacology

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The two major nicotinic acetylcholine receptors (nAChRs) in the brain are the a4b2 and a7 subtypes. A "methyl scan" of the pyrrolidinium ring was used to detect differences in nicotine's interactions with these two receptors. Each methylnicotine was investigated using voltage-clamp and radioligand binding techniques. Methylation at each ring carbon elicited unique changes in nicotine's receptor interactions. Replacing the 19-N-methyl with an ethyl group or adding a second 19-N-methyl group significantly reduced interaction with a4b2 but not a7 receptors. The 29-methylation uniquely enhanced binding and agonist potency at a7 receptors. Although 39-and 59-trans-methylations were much better tolerated by a7 receptors than a4b2 receptors, 49-methylation decreased potency and efficacy at a7 receptors much more than at a4b2 receptors. Whereas cis-59-methylnicotine lacked agonist activity and displayed a low affinity at both receptors, trans-59-methylnicotine retained considerable a7 receptor activity. Differences between the two 59-methylated analogs of the potent pyridyl oxymethylene-bridged nicotine analog A84543 were consistent with what was found for the 59-methylnicotines. Computer docking of the methylnicotines to the Lymnaea acetylcholine binding protein crystal structure containing two persistent waters predicted most of the changes in receptor affinity that were observed with methylation, particularly the lower affinities of the cis-methylnicotines. The much smaller effects of 19-, 39-, and 59-methylations and the greater effects of 29and 49-methylations on nicotine a7 nAChR interaction might be exploited for the design of new drugs based on the nicotine scaffold. SIGNIFICANCE STATEMENTUsing a comprehensive "methyl scan" approach, we show that the orthosteric binding sites for acetylcholine and nicotine in the two major brain nicotinic acetylcholine receptors interact differently with the pyrrolidinium ring of nicotine, and we suggest reasons for the higher affinity of nicotine for the heteromeric receptor. Potential sites for nicotine structure modification were identified that may be useful in the design of new drugs targeting these receptors.The views presented in this article are those of the authors and do not necessarily reflect those of the US Food and Drug Administration. No official endorsement is intended nor should be inferred.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

A Methyl Scan of the Pyrrolidinium Ring of Nicotine Reveals Significant Differences in Its Interactions with α7 and α4β2 Nicotinic Acetylcholine Receptors

Xiao

Andrud

Soti

et al. 2020

Molecular Pharmacology

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“…21 NOR is protonated on the pyrrolidine nitrogen (Pyrro–NOR-H + ) in water at physiological pH, similar to NIC. 22 However, the gas-phase acidity of NOR, determined by FT-ICR, suggests that NOR-H + has only a pyridine-protomer (Pyri–NOR-H + ) in the gas phase. 11 No IR/UV spectroscopic study has been reported to date for gas-phase NOR-H + , and therefore its protonation site in the gas phase has not unambiguously been determined yet.…”

Section: Introductionmentioning

confidence: 99%

Gas phase protonated nicotine is a mixture of pyridine- and pyrrolidine-protonated conformers: implications for its native structure in the nicotinic acetylcholine receptor

Takeda

Hirata

Tsuruta

et al. 2022

Phys. Chem. Chem. Phys.

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“…This may also apply to the binding of nicotine to the lobster ACBM since the decline in binding above pH 7.5 may be caused by the progressive deprotonation of the pyrrolidine nitrogen of nicotine, whose pKa is 8.1 (Fujita, Nakajima, Soeda & Yamamoto, 1971). However, the observed increase in affinity of the ACBM for nicotine with increasing salt concentration is contrary to the effect on simple electrostatic interactions that would be expected by increasing the ionic strength.…”

Section: Discussionmentioning

confidence: 96%

Interactions between ions and the axon plasma membrane: Effects of cations and anions on the axonal cholinergic binding macromolecule of lobster nerves

Denburg

1973

J. Membrain Biol.

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Summary. It has been demonstrated that cations and ions interact directly with the axonal cholinergic binding macromolecule (ACBM) from lobster walking leg nerves. This interaction results in an increased affinity for binding of [3H] nicotine. The action sequence for the enhancement effect is Na + >K + >Li + >Rb+> Cs + while the anion sequence is I-> Br -> CI-> F-. These results have been interpreted in terms of Eisenman's theory of equilibrium cation specificity in an attempt to acquire information about the ion binding sites on the ACBM. The mechanism of the enhancement of nicotine binding to the ACBM may serve as a model for studying the conformational changes arising from binding of ions to axonal macromolecules.As an alternative to the concept of separate Na + and K + gates or channels through which flow the cation currents that produce an axonal action potential, some models have been proposed (Tasaki, 1968;Weiss, 1969) which postulate a general increase in cation permeabilities caused by a cation exchange process generating a conformational change in the membrane.One approach in attempting to distinguish between these various theories is to study the interaction between the cations and the axon plasma membrane. Direct binding studies of Na § and K § are not feasible because the relatively low affinity of their binding and low concentration of binding sites makes equilibrium dialysis difficult and the presumably rapid equilibrium between cation and membrane prevents isolation of cation-membrane complexes. It was observed that the binding of [3H] nicotine to the axonal cholinergic binding macromolecule (ACBM), from the walking leg nerve

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Physicochemical properties of biological interest and structure of nicotine and its related compounds

Cited by 23 publications

References 12 publications

A Methyl Scan of the Pyrrolidinium Ring of Nicotine Reveals Significant Differences in Its Interactions with α7 and α4β2 Nicotinic Acetylcholine Receptors

A Methyl Scan of the Pyrrolidinium Ring of Nicotine Reveals Significant Differences in Its Interactions with α7 and α4β2 Nicotinic Acetylcholine Receptors

Gas phase protonated nicotine is a mixture of pyridine- and pyrrolidine-protonated conformers: implications for its native structure in the nicotinic acetylcholine receptor

Interactions between ions and the axon plasma membrane: Effects of cations and anions on the axonal cholinergic binding macromolecule of lobster nerves

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