The iodomethylation of nicotine. An unusual example of competitive nitrogen alkylation

Seeman, Jeffrey I.; Whidby, Jerry F.

doi:10.1021/jo00886a011

Cited by 43 publications

(25 citation statements)

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“…3) was found to correspond with published data (27). The unlabeled pure NIM residue analyzed by NMR (Fig.…”

Section: C343supporting

confidence: 84%

“…[14C]Choline has been found to penetrate the adult rat BBB (BUI 6.27 ± 0.3) by a very-low-capacity carrier system, Km = 442 + 60 ,uM (30) Values for the first two choline listings were obtained from Oldendorf et al (27), while the values for the bottom choline listing were obtained from Oldendorf et al (25); and values for nicotine were obtained from Oldendorf et al (2). tCaps, [3-(cyclohexylamino)propanesulfonic acid].…”

Section: C343mentioning

confidence: 99%

See 1 more Smart Citation

Blood-brain barrier penetration abolished by N-methyl quaternization of nicotine.

Oldendorf¹,

Stoller²,

Harris³

1993

Proc. Natl. Acad. Sci. U.S.A.

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The present study determined the effect of organically quaternizing either ofthe two tertiary nitrogen sites of nicotine to assess the in vivo effects of the permanently ionized states of the synthesized N-[14C]methylnicotines on brain uptake in rat after intracarotid i jection. Male SpragueDawley rats were used to measure the brain uptake index (BUI) by single-pass clearance in brain after rapid in'ection at pH 7.4 into the left common carotid artery (expressed as a percentage) relative to simultaneously injected 3HOH. The BUI 6f ["4CImannitol, a control for the method background, was measured to be 2.6 + 0.6. At physiological pH, in striking contrast to the [pyrroldine-2-14C]nicotine BUI of 120 ±s3, the N-["4C]-methylnicotines had a BUI of 3.0 ± 0.6, which was not significantly different from the method background and which indicated abolition of blood-brain barrier penetration of nicotine with the sensitivity of the BUI method.Many alkaloids contain nitrogen(s) that exist in a positively charged form at physiological pH. Many of these substances are also known to have considerable brain uptake (1). In a study of [pyrrolidine-2-"4C]nicotine at various pH values from 4.7 to 10.4, the brain uptake index (BUI), values varied from 49 ± 10 to 127 ± 5, according to the fraction of neutral (uncharged) nicotine molecules available for blood-brain barrier (BBB) penetration (2). The present study was undertaken to determine iforganic quaternization ofeither nitrogen or nicotine would reduce the fraction of neutral nicotine and its penetration ofthe BBB at physiological pH 7.4 by the BUI method.Prior reports have reviewed theoretical or experimental factors that influence nicotine activity, quaternary nicotine ions, and uncharged molecules at physiological pH values (3)(4)(5)(6)(7). Pharmacological studies have found that the effects of N-methylnicotines were apparently confined to the peripheral nervous system (8-14). Many biological studies have suggested, based upon the occurrence of peripheral effects without central effects, that N-methylnicotines did not penetrate the BBB (15-19). Studies of nicotine metabolites in a number of species have shown the presence of N-methylnicotines (20-23).In the present study nicotine was methylated with [14C]-methyl iodide to synthesize two quaternized and therefore permanently charged cationic derivatives. These quaternized derivatives were nicotine isomethiodide (NIM), in which the pyridine nitrogen was methylated, and nicotine monomethiodide (NMI) in which the pyrrolidine nitrogen was methylated. High-pressure liquid chromatographic (HPLC) procedures were developed to assay these derivatives; product structure was confirmed by nuclear magnetic resonance (NMR) spec- MATERIALS AND METHODS Animals. Studies were performed with 250-to 300-g adult male Sprague-Dawley rats (Harlan-Sprague-Dawley) that were housed in a temperature/humidity/light-controlled (6:00 a.m. to 6:00 p.m.) animal room with free access to food and water until the morning of the experiment. Burdick and Jac...

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“…3) was found to correspond with published data (27). The unlabeled pure NIM residue analyzed by NMR (Fig.…”

Section: C343supporting

confidence: 84%

Section: C343mentioning

confidence: 99%

Blood-brain barrier penetration abolished by N-methyl quaternization of nicotine.

Oldendorf¹,

Stoller²,

Harris³

1993

Proc. Natl. Acad. Sci. U.S.A.

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“…Moreover, this mixture reduced carbene complexes 4a,b to give the expected nicotinium ylide complexes in high yield. [28] Although the synthesis of N-methyl-1,2-dihydronicotine from the known N-methylnicotinium iodide [52] failed, the reduction of the known [53] N-benzylnicotinium bromide (70) with sodium dithionite led to N-benzyl Scheme 26).…”

Section: Stereogenic Center On a Substituent Of The Pyridine Ring: Symentioning

confidence: 99%

Interaction of Dihydropyridines and Nucleophiles with Carbene Complexes of Chromium: Diastereo‐ and Enantioselective Synthesis of Polycyclic Butenolides

Rudler¹,

Parlier²,

Certal³

et al. 2004

Eur J Org Chem

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The interaction of N‐methyldihydropyridine with carbene complexes of chromium promotes their spontaneous homologation upon addition of a hydride to the carbene carbon and an insertion of CO. This is followed in the case of complexes tethered to a triple bond by cascade insertions of the triple bond and of a CO ligand giving finally butenolides. The scope of the reaction has been established with its limitations, together with the stereochemical outcome, which is discussed. [5.5], [5.6], [5.7] bicyclic and tricyclic systems have been synthesised together with chiral butenolides starting from chiral carbene complexes. Most of the new structures have been assessed by X‐ray crystallography. This transformation was first extended to dihydronicotinamides, to chiral dihydropyridines such as dihydronicotines which led to the butenolides in an enantioselective way, and to other sources of hydrides. Second, a series of nucleophiles such as alkoxides, alkyllithium and alkylmagnesium compounds led also to polycyclic, substituted butenolides. Moreover, the final lactone enolates could be trapped with oxygen and gave unsaturated lactonols. The key point in all of these reactions is the formation of tetrahedral intermediates upon interaction of the nucleophiles with the carbene carbon. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2004)

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“…We have shown (3,6) that treatment of nicotine with less than one equivalent of iodomethane leads to both N'-methylnicotinium iodide and Nmethylnicotinium iodide in a ratio of 2.2:l even though nicotine's pyrrolidine nitrogen is considerably more basic than its pyridine nitrogen (pKa 7.8, pK 3.04). In addition, we observed that iodomethylation of nicotine with one equivalent of iodomethane results in dialkylation products and unreacted starting material (3,6). These three suggestions may explain reports of low nicotine yields on iodomethylation of nornicotine (4b, 4d, 4e, 5).…”

Section: Resultsmentioning

confidence: 98%

“…As part of o u r study of the structure (1,2) and chemical reactivity ( 3 ) of nicotine (1) and related compounds, we required moderate quantities of a number of N-CD3 labelled nicotine analogues ( 4 ) ( e . g .…”

Section: Introductionmentioning

confidence: 99%

Convenient syntheses of N‐CD₃ labelled nicotine and nicotine analogues

Seeman

Secor

Forrest

1979

Labelled Comp Radiopharmac

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The iodomethylation of nicotine. An unusual example of competitive nitrogen alkylation

Cited by 43 publications

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Blood-brain barrier penetration abolished by N-methyl quaternization of nicotine.

Blood-brain barrier penetration abolished by N-methyl quaternization of nicotine.

Interaction of Dihydropyridines and Nucleophiles with Carbene Complexes of Chromium: Diastereo‐ and Enantioselective Synthesis of Polycyclic Butenolides

Convenient syntheses of N‐CD₃ labelled nicotine and nicotine analogues

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The iodomethylation of nicotine. An unusual example of competitive nitrogen alkylation

Cited by 43 publications

References 0 publications

Blood-brain barrier penetration abolished by N-methyl quaternization of nicotine.

Blood-brain barrier penetration abolished by N-methyl quaternization of nicotine.

Interaction of Dihydropyridines and Nucleophiles with Carbene Complexes of Chromium: Diastereo‐ and Enantioselective Synthesis of Polycyclic Butenolides

Convenient syntheses of N‐CD3 labelled nicotine and nicotine analogues

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Convenient syntheses of N‐CD₃ labelled nicotine and nicotine analogues