Nicotine enantiomers

PA Crooks. N-methylation of nicotine enantiomers by human liver cytosol. J Pharm Pharmacol 40 153—154,1988. 

The structure of 7a-(3-pyrrolidinyl)-hexahydro-l//-pyr-rolizine (8) can be conceptualized as a hybrid between the individual enantiomers of nicotine. Pyrrolizidine 8 was synthesized in straightforward fashion by addition of the pyridyl lithium anion to the readily prepared imminium salt (Eq. (1)) (Wasicak et al., 1998). Compound 8 displays subnanomolar binding affinity (K = 0.32 nM) for a4 2 receptors, which is a 3-fold increase in binding affinity over (S)-nicotine (1) and a 60-fold increase relative to the less potent (/ )-nicotine enantiomer. One advantage with heterocyclic substituted pyrrolizidines series over their pyrrolidine counterparts is that no stereochemical issues come into play since they are symmetrical molecules. 

Vildiz, D-, Ercal, N., and Armstrong, D. W. (1998). Nicotine enantiomers and oxidative stress. Toxicology 1311, 155-165. 

T Hummel, C Hummel, E Pauli, G Kobal. Olfactory discrimination of nicotine-enantiomers by smokers and non-smokers. Chem Senses 17 13-21, 1992. 

The term chiral recognition refers to a process m which some chiral receptor or reagent interacts selectively with one of the enantiomers of a chiral molecule Very high levels of chiral recognition are common m biological processes (—) Nicotine for exam pie IS much more toxic than (+) nicotine and (+) adrenaline is more active than (—) adrenaline m constricting blood vessels (—) Thyroxine an ammo acid of the thyroid gland that speeds up metabolism is one of the most widely used of all prescription... 

Syntheses of naphthyridone derivatives follow the same procedures as those of quinolones, except that substituted 2-aminopyridines (Gould-Jacobs modification) or substituted nicotinic ester/nicotinoyl chloride are used instead of anilines or o-halobenzoic acid derivatives. Most of the recently introduced quinolone antibacterials possess bicyclic or chiral amino moieties at the C-7 position, which result in the formation of enantiomeric mixtures. In general, one of the enantiomers is the active isomer, therefore the stereospecific synthesis and enantiomeric purity of these amino moieties before proceeding to the final step of nucleophilic substitution at the C-7 position of quinolone is of prime importance. The enantiomeric purity of other quinolones such as ofloxacin (a racemic mixture) plays a major role in the improvement of the antibacterial efficacy and pharmacokinetics of these enan-... 

No difference has been observed in the interactions of the two enantiomers of isoflurane with hpid bilayers. But the (5)-enantiomer of isoflurane is two times more active than the (7 )-enantiomer toward a calcium channel receptor, that is sensitive to volatile anesthetic agents, while nodifference in activity has been observed toward an anesthetic nonsensitive receptor. The (5)-enantiomer of isoflurane is also more active than the (R)-enantiomer toward acetylcholine nicotinic receptor and GABA receptor. These data strongly suggest that fluoroethers interact not only with cerebral membranous lipids but also with receptor proteins. 

Chromatography. Under certain conditions, even homochiral and het-erochiral self-assemblies can be separated by achiral methods. Thus, chromatography of partially resolved enantiomers can cause depletion or enrichment of enantiomers on achiral stationary phases with an achiral mobile phase. 14C-Labeled nicotine was first resolved into its enantiomers by high-performance liquid chromatography (HPLC) on an achiral stationary phase (Partisil-ODS or -SCX) through coinjection with optically active nicotine (59). This observation was followed by resolution of a number of chiral compounds by chromatography (<50-62) (Scheme 34). When a chiral diamide in 74% ee was separated on a Kieselgel 60... 

Both coniine and nicotine have one stereocenter, and two possible stereoisomers (one pair of enantiomers). 

The structure of onychine, an alkaloid of Onychopetalum amazonicum that has hitherto been formulated as (33), must be revised to (34). Both structures have been synthesized the former was found to be different from onychine and the latter identical with it.33 Three stereospecific syntheses of sesbanine (35) have been reported. In one, 4-(methoxycarbonyl)nicotinic acid is the starting point (Scheme 3).34 The other two both start from 4-methylnicotinonitrile, one35 leading to ( )-sesbanine and the other to the (+)-enantiomer.35 10-Deoxyses-banine has also been synthesized, by a route which appears applicable to the alkaloid itself.37... 

An unexpected but possibly related phenomenon is the separation of enantiomers of nicotine in a totally achiral system [256]. The mechanism is unclear but may involve the formation of in situ diastereometric dimers, where a dimer formed from the same two enantiomers could possibly resolve from a racemic dimer. 

K. C. Cundy and P. A. Crook, Unexpected phenomenon in the high-performance liquid chromatographic analysis of racemic Relabelled nicotine, separation of enantiomers in a totally achiral system, J. Chromatogr., 281 11 (1983). 

The naturally occurring enantiomer, (+)-anatoxin-a, is much more potent than (—)-anatoxin-a [38]. For example, using conditions that preferentially labeled rat brain a4p2 nACh receptors with [ H]nicotine, the natural enantiomer was found to be 1000-fold more potent than (—[-anatoxin [39]. This enantiospecificity of anatoxin-a has provided an excellent tool for probing the stereospedfidty of the ACh binding site on the nicotinic receptor. 

Naturally occurring levorotatory nicotine (4) has the S- absolute configuration. Its enantiomer, R-(+)-nicotine, was decidedly less potent than the naturally occurring material in assays for peripheral effects (99). The pyrrolidine methyl quaternary derivative of S-(-)-nicotine (50) shows peripheral activity com-... 

Nomicotine, in which the N-methyl is replaced by hydrogen, is somewhat less potent and active than nicotine in most assays (102). R- and S-nomicotine are equipotent with R-(+)-nicotine,the less active, unnatural enantiomer, in a rat brain membrane-binding assay (103). In that study, S-(-)-nicotinewas 13 times more potent than its R- enantiomer. Replacement of the N-methyl of nicotine with ethyl or n-propyl eauses an exponential loss of peripheral nicotinic effect (102). Anabasine (51), a relatively minor alkaloidal constituent of tobacco, demonstrated approximately 1/10 the affinity of nicotine in a binding assay (104). A synthetic azetidine congener (52) of nicotine binds with the same affinity as nicotine to rat brain membrane tissue, and it displayed a greater potency than nicotine in a rat behavioral assay (105). Evaluation of a series of 6-substituted nicotine derivatives (53) led to the conclusion that affinity for rat brain... 

The R-enantiomer of the pyridylquinucli-dine (62)has a slightly higher affinity for nicotinic sites than the S-enantiomer (109). 

The (+)-cis isomer of (108) was the most potent muscarinic of the series. It demonstrated a eudismic ratio of the same high order of magnitude as that for muscarine and the dioxolanes. This (+)-cis enantiomer has the same absolute configuration as the muscarini-cally most active L-(+)-muscarine (2) and the (+)-cis-dioxolane (109). The other isomers represented by structure (108), although much less potent than the (+)-cis isomer, also demonstrated a degree of muscarinic agonist effect. All four isomers of structure (108) showed similar nicotinic potency and activity, close to that of carbamyl choline, and eudismic ratios were small. 

Compound (110) is exponentially less potent than (11 l)at muscarinic receptors. Both compounds demonstrate low nicotinic potency and activity. The sulfone congeners (112) of the enantiomers (212,5JR and 2S,5S) of the cis-structure are weak muscarinics with a eudismic ratios of unity. 

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