Nornicotine

Nornicotine
Names
	IUPAC name 3-[(2S)-2-Pyrrolidinyl]pyridine
	Other names Demethylnicotine
Identifiers
CAS Number	494-97-3 ;
3D model (JSmol)	Interactive image;
ChemSpider	82588;
ECHA InfoCard	100.165.066
PubChem CID	91462;
UNII	83H6L5QD8Z ;
CompTox Dashboard (EPA)	DTXSID50862034 ;
	InChI InChI=1S/C9H12N2/c1-3-8(7-10-5-1)9-4-2-6-11-9/h1,3,5,7,9,11H,2,4,6H2/t9-/m0/s1 Key: MYKUKUCHPMASKF-VIFPVBQESA-N; InChI=1/C9H12N2/c1-3-8(7-10-5-1)9-4-2-6-11-9/h1,3,5,7,9,11H,2,4,6H2/t9-/m0/s1 Key: MYKUKUCHPMASKF-VIFPVBQEBM;
	SMILES n1cccc(c1)[C@H]2NCCC2;
Properties
Chemical formula	C9H12N2
Molar mass	148.209 g·mol−1
	Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa). Infobox references

Nornicotine is an alkaloid found in various plants including Nicotiana, the tobacco plant.^[1] It is chemically similar to nicotine, but does not contain a methyl group.

It is a precursor to the carcinogen N-nitrosonornicotine that is produced during the curing and processing of tobacco.^[2] Nornicotine can react in human saliva to form N-nitrosonornicotine,^[3] a known type 1 carcinogen.^[4]

Synthesis

There are several routes for the synthesis of nornicotine. One route is the demethylation of nicotine, which can be accomplished by reaction with silver oxide.^[5]

\mathrm {\xrightarrow[{H_{2}O}]{Ag_{2}O}}

Another route is the partial reduction of 3-myosmine, which can be accomplished by standard catalytic hydrogenation conditions using palladium as a catalyst^[6] or with sodium borohydride.^[7] This reaction gives the racemic product.

\mathrm {\xrightarrow[{H_{2}}]{Pd/C}}

Pharmacology

Nornicotine possess high affinity for alpha-6 and alpha-7 subunits of nAChRs.^[8] It also inhibits DAT in striatum via nAChR and releases dopamine in rats.^[9]^[10]^[11]

References

^ Laszlo C, Kaminski K, Guan H, Fatarova M, Wei J, Bergounioux A, Schlage WK, Schorderet-Weber S, Guy PA, Ivanov NV, Lamottke K, Hoeng J (November 2022). "Fractionation and Extraction Optimization of Potentially Valuable Compounds and Their Profiling in Six Varieties of Two Nicotiana Species". Molecules. 27 (22): 8105. doi:10.3390/molecules27228105. PMC 9694777. PMID 36432206.
^ Siminszky, B. (2005). "Conversion of nicotine to nornicotine in Nicotiana tabacum is mediated by CYP82E4, a cytochrome P450 monooxygenase". Proceedings of the National Academy of Sciences. 102 (41): 14919–24. doi:10.1073/pnas.0506581102. PMC 1253577. PMID 16192354.
^ Knezevich A, Muzic J, Hatsukami DK, Hecht SS, Stepanov I (February 2013). "Nornicotine nitrosation in saliva and its relation to endogenous synthesis of N'-nitrosonornicotine in humans". Nicotine & Tobacco Research. 15 (2): 591–5. doi:10.1093/ntr/nts172. PMC 3611998. PMID 22923602.
^ "List of Classifications – IARC Monographs on the Identification of Carcinogenic Hazards to Humans". monographs.iarc.fr. Retrieved 2020-07-22.
^ Spaeth (1936). "Über dasd-Nor-nicotin". Chem. Ber. 69 (2): 250–251. doi:10.1002/cber.19360690207.
^ Haines (1945). "Chemical Reactivity of Myosmine". J. Am. Chem. Soc. 67 (8): 1258–1260. doi:10.1021/ja01224a011.
^ Dickerson, TJ; Janda, KD (2002). "Aqueous aldol catalysis by a nicotine metabolite". J. Am. Chem. Soc. 124 (13): 3220–1. doi:10.1021/ja017774f. PMID 11916401..
^ Papke RL, Dwoskin LP, Crooks PA (April 2007). "The pharmacological activity of icotine and nornicotine on nAChRs subtypes: relevance to nicotine dependence and drug discovery". Journal of Neurochemistry. 101 (1): 160–7. doi:10.1111/j.1471-4159.2006.04355.x. PMID 17241116.
^ Middleton LS, Crooks PA, Wedlund PJ, Cass WA, Dwoskin LP (March 2007). "Nornicotine inhibition of dopamine transporter function in striatum via nicotinic receptor activation". Synapse. 61 (3): 157–65. doi:10.1002/syn.20351. PMID 17146768. S2CID 35071082.
^ Dwoskin LP, Teng LH, Crooks PA (September 2001). "Nornicotine, a nicotine metabolite and tobacco alkaloid: desensitization of nicotinic receptor-stimulated dopamine release from rat striatum". European Journal of Pharmacology. 428 (1): 69–79. doi:10.1016/s0014-2999(01)01283-3. PMID 11779039.
^ Dwoskin LP, Buxton ST, Jewell AL, Crooks PA (June 1993). "S(-)-nornicotine increases dopamine release in a calcium-dependent manner from superfused rat striatal slices". Journal of Neurochemistry. 60 (6): 2167–74. doi:10.1111/j.1471-4159.1993.tb03502.x. PMID 8492124. S2CID 25622404.

[1] Laszlo C, Kaminski K, Guan H, Fatarova M, Wei J, Bergounioux A, Schlage WK, Schorderet-Weber S, Guy PA, Ivanov NV, Lamottke K, Hoeng J (November 2022). "Fractionation and Extraction Optimization of Potentially Valuable Compounds and Their Profiling in Six Varieties of Two Nicotiana Species". Molecules. 27 (22): 8105. doi:10.3390/molecules27228105. PMC 9694777. PMID 36432206.

[2] Siminszky, B. (2005). "Conversion of nicotine to nornicotine in Nicotiana tabacum is mediated by CYP82E4, a cytochrome P450 monooxygenase". Proceedings of the National Academy of Sciences. 102 (41): 14919–24. doi:10.1073/pnas.0506581102. PMC 1253577. PMID 16192354.

[:1-3] Knezevich A, Muzic J, Hatsukami DK, Hecht SS, Stepanov I (February 2013). "Nornicotine nitrosation in saliva and its relation to endogenous synthesis of N'-nitrosonornicotine in humans". Nicotine & Tobacco Research. 15 (2): 591–5. doi:10.1093/ntr/nts172. PMC 3611998. PMID 22923602.

[:2-4] "List of Classifications – IARC Monographs on the Identification of Carcinogenic Hazards to Humans". monographs.iarc.fr. Retrieved 2020-07-22.

[späth-5] Spaeth (1936). "Über dasd-Nor-nicotin". Chem. Ber. 69 (2): 250–251. doi:10.1002/cber.19360690207.

[6] Haines (1945). "Chemical Reactivity of Myosmine". J. Am. Chem. Soc. 67 (8): 1258–1260. doi:10.1021/ja01224a011.

[7] Dickerson, TJ; Janda, KD (2002). "Aqueous aldol catalysis by a nicotine metabolite". J. Am. Chem. Soc. 124 (13): 3220–1. doi:10.1021/ja017774f. PMID 11916401..

[pmid17241116-8] Papke RL, Dwoskin LP, Crooks PA (April 2007). "The pharmacological activity of icotine and nornicotine on nAChRs subtypes: relevance to nicotine dependence and drug discovery". Journal of Neurochemistry. 101 (1): 160–7. doi:10.1111/j.1471-4159.2006.04355.x. PMID 17241116.

[pmid17146768-9] Middleton LS, Crooks PA, Wedlund PJ, Cass WA, Dwoskin LP (March 2007). "Nornicotine inhibition of dopamine transporter function in striatum via nicotinic receptor activation". Synapse. 61 (3): 157–65. doi:10.1002/syn.20351. PMID 17146768. S2CID 35071082.

[pmid11779039-10] Dwoskin LP, Teng LH, Crooks PA (September 2001). "Nornicotine, a nicotine metabolite and tobacco alkaloid: desensitization of nicotinic receptor-stimulated dopamine release from rat striatum". European Journal of Pharmacology. 428 (1): 69–79. doi:10.1016/s0014-2999(01)01283-3. PMID 11779039.

[pmid8492124-11] Dwoskin LP, Buxton ST, Jewell AL, Crooks PA (June 1993). "S(-)-nornicotine increases dopamine release in a calcium-dependent manner from superfused rat striatal slices". Journal of Neurochemistry. 60 (6): 2167–74. doi:10.1111/j.1471-4159.1993.tb03502.x. PMID 8492124. S2CID 25622404.

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