Chiral anesthetics

Meinwald and Pearson in collaboration with K5nig made another advancement in the field of chiral anesthetics when they discovered that these molecules could be resolved on an analytical scale using capillary gas chromatography (GC) on derivatized cyclodextrin stationary phases (. Before 3iis method became available, the only method of determining the enantiomeric purity of the anesthetics was based on optical rotation. Because the optical rotations of halothane and enflurane are not large, uncertainty and inaccuracy were sure to have plagued these results. This new GC method allows quick and accurate... 

Gas chromatography (GC) has also been used for preparative purposes, but is restricted to relatively volatile racemates such as anesthetics, pheromones or monoterpenes and, therefore, very few applications are reported. Nevertheless, in the cases to which GC may be applied, it could be considered as an economical alternative to HPLC. Most of the resolutions of enantiomers were performed on cyclodex-trin-derived CSPs [109, 144-153], and only on very few occasions were other chiral selectors used [153]. 

Prilocaine (4.138), a chiral local anesthetic, was hydrolyzed stereoselec-tively at its amide bond. Indeed, the plasma concentrations of the (-)-(/ )-enantiomer were lower than those of the (+)-(5 )-enantiomer after i.v. administration in the cat. In vitro studies of liver preparations from various mammals confirmed that the (R)-isomer was hydrolyzed at much higher rates than the (.S )-form [84],... 

Cyclic amines (including local anesthetic drugs) and amides were among the first classes of chiral compounds investigated in the early stages of the application of macrocyclic antibiotics as chiral selectors therefore, they were screened on vancomycin [7], teicoplanin [30], and ristocetin A [33] CSPs, under RPmode systems. Cyclic imides (including barbiturates, piperidine-2,6-diones, and mephenytoin) have been separated on a vancomycin CSP [157], under NP and RP mobile phase conditions. 

Ropivacaine hydrochloride is a long-acting local anesthetic, which is manufactured as the pure S-enantiomer. The enantiomeric purity is determined by CZE, using heptakis-(2,6-di-0-methyl)-j5-cyclodextrin as chiral selector. A resolution of 3.7 between the two enantiomers is required for the system suitability solution. The percentage R-enantiomer is calculated relative to the S-enantiomer in the same electropherogram, and should not exceed 0.5%. In Eigure 5, a representative electropherogram is presented. 

Two-level full factorial designs were used to determine the CE robusmess of a chiral separation of the local anesthetic ropivacaine in injection solutions and of a separation of the macrolide antibiotic tylosin and its main related substances. Table 13a shows the applied... 

Javerfalk, E. M., Amini, A., Westerlund, D., and Andren, P. E. (1998). Chiral separation of local anesthetics by a capillary electrophoresls/partlal filling technique coupled online to microelectrospray mass spectrometry. /. Mass Spectrom. 33, 183 — 186. 

Several general anesthetics (isoflurane, ketamine, thiopental, etomidate) have one or more chiral carbons and thus exist as pairs ot stereoisomers. In many cases one stereoisomer is more potent than the other at providing anesthesia despite little difference in pharmacokinetics (Christensen Lee, 1973 Benthuysen et ak, 1989 Harris et ak, 1992 Dickinson et ak, 1994). The stereoisomers have equal hydrophobic properties and partition equally into the membrane. 

The more active enantiomer at one type of receptor site may not be more active at another receptor type, eg, a type that may be responsible for some other effect. For example, carvedilol, a drug that interacts with adrenoceptors, has a single chiral center and thus two enantiomers (Figure 1-2, Table 1-1). One of these enantiomers, the (S) -) isomer, is a potent B-receptor blocker. The (R)(+) isomer is 100-fold weaker at the receptor. However, the isomers are approximately equipotent as -receptor blockers. Ketamine is an intravenous anesthetic. The (+) enantiomer is a more potent anesthetic and is less toxic than the (-) enantiomer. Unfortunately, the drug is still used as the racemic mixture. 

Key Words Preparative-scale GC, enantiomeric separation, chiral stationary phases, SMB-GC, nitrogen invertomer, inhalation anesthetics, terpenoids, flavours,... 

Juza, M, Braun, M., and Schurig, V. (1997) Preparative enantiomer separation of the chiral inhalation anesthetics enfiurane, isoflurane and desflurane by gas chromatography on a derivatized 7-cyclodextrin stationary phase, J. Chromatogr. A 769, 119-127. 

Juza, M, Biressi, G., Di Giovanni, O., Mazzotti, M., Schurig, V., and Morbidelli, M. (1998b) Resolution of the inhalation anesthetic enfiurane on a cyclodextrin-based chiral stationary phase development of the GC-SMB separation, in F. Mennier (ed.), Fundamentals of Adsorption, Elsevier, Amsterdam, pp. 455-460. 

Schmidt, R., Roeder, M., Oeckler, 0., Simon, A., and Schurig, V. (2000) Separation and absolute configuration of the enantiomers of a degradation product of the new inhalation anesthetic sevoflurane. Chirality 12, 751-755. 

Wang, F., Polavarapu, P. L., Schurig. V., and Schmidt, R. (2002) Absolute configuration and conformational analysis of a degradation product of the inhalation anesthetic sevoflurane a vibrational circular dichroism study. Chirality, 14, 618-624. 

Currently there is a trend toward the synthesis and large-scale production of a single active enantiomer in the pharmaceutical industry [61-63]. In addition, in some cases a racemic drug formulation may contain an enantiomer that will be more potent (pharmacologically active) than the other enantiomer(s). For example, carvedilol, a drug that interacts with adrenoceptors, has one chiral center yielding two enantiomers. The (-)-enantiomer is a potent beta-receptor blocker while the (-i-)-enantiomer is about 100-fold weaker at the beta-receptor. Ketamine is an intravenous anesthetic where the (+)-enantiomer is more potent and less toxic than the (-)-enantiomer. Furthermore, the possibility of in vivo chiral inversion—that is, prochiral chiral, chiral nonchiral, chiral diastereoisomer, and chiral chiral transformations—could create critical issues in the interpretation of the metabolism and pharmacokinetics of the drug. Therefore, selective analytical methods for separations of enantionmers and diastereomers, where applicable, are inherently important. 

The main applications of enantiomeric separation by GC concern precise determination of enantiomeric composition of chiral research chemicals, drugs, intermediates, metabolites, pesticides, flavors and fragrances, etc. CHIRBASE, a database of chiral compounds, provides comprehensive structural, experimental, and bibliographic information on successful and unsuccessful chiral separations, and rule sets for each CSP and information about the processes of chiral separations. According to CHIRBASE, an appropriate CSP is available for almost every racemic mixture of compounds ranging form apolar to polar. Some 22,000 separations of enantiomers, involving 5,500 basic chiral compounds and documented in 2,200 publications, have been achieved by GC. This method is particularly suitable for volatile compounds such as inhalation anesthetic agents, e.g., enflurane, isoflurane, desflurane, and racemic a-ionone. 

The enantiomeric separation of some racemic antihistamines and antimalar-ials, namely (+/-)-pheniramine, (+/-)-bromopheniramine, (+/-)-chlorophen-iramine, (+/-)-doxylamine, and (+/-)-chloroquine, were investigated by capillary zone electrophoresis (CZE). The enantiomeric separation of these five compounds was obtained by addition of 7 mM or 1 % (w/v) of sulfated P-cyclo-dextrin to the buffer as a chiral selector. It was found that the type of substituent and degree of substitution on the rim of the cyclodextrin structure played a very important part in enhancing chiral recognition (174). The use of sulfated P-cyclo-dextrin mixtures as chiral additives was evaluated for the chiral resolution of neutral, cyclic, and bicyclic monoterpenes. While there was no resolution of the monoterpene enantiomers with the sulfated P-cyclodextrin, the addition of a-cyclodextrin resulted in mobility differences for the terpenoid enantiomers. Resolution factors of 4-25 were observed. The role of both a-cyclodextrin and sulfated P-cyclodextrin in these separations was discussed (187). The enantiomeric separation of 56 compounds of pharmaceutical interest, including anesthetics, antiarrhythmics, antidepressants, anticonvulsants, antihistamines, antimalarials, relaxants, and broncodilators, was studied. The separations were obtained at pH 3.8 with the anode at the detector end of the capillary. Most of the 40 successfully resolved enantiomers contained a basic functionality and a stereogenic carbon (173). 

It is found that by limiting consideration to molecules with only one chiral center and therefore only one pair of enantiomers the usual physical and chemical properties are identical in a symmetrical environment. However, rates of reactions, even reactivity (e.g., metabolism reactions) and binding propensities may differ significantly in an asymmetric bioenvironment. There are cases where no differences are demonstrable. Both + and -cocaine are equipotent local anesthetics. Similarly, both enantiomers of chloroquine are equally effective antimalarial compounds. It is possible that in these instances the centers of asymmetry do not participate in drug-receptor interactions, or, more likely, that the interaction may involve only one or two points of contact. 

GC is basically a technique for analytical enantioseparations. However, micropreparative separations are also feasible using this technique. The most impressive example of the application of chiral GC for micropreparative enantioseparation of drug enantiomers is the chiral inhalation anesthetic drug, enflurane. According to recent data, the enantiomers of isoflurane may have different pharmacological properties [94]. For the isomeric compound enflurane (Fig. 3) a more intensive metabolism was established for the (ft)-(-)-enantiomer compared with the (S)-(+)-enantiomer [95]. Enflurane is a gas and therefore, the most favorable method for the enantioseparation will certainly be GC. Analytical-scale enantioseparations of this compound have been reported using various CD derivatives as CSPs [97]. The micro-... 

Figure 3. Structure of chiral inhalation anesthetic enflurane [100],...

UNDESIRED EEEECTS OF LOCAL ANESTHETICS In addition to blocking conduction in nerve axons in the peripheral nervous system, local anesthetics interfere with the function of all organs in which conduction or transmission of impulses occurs. Thus, they have important effects on the CNS, autonomic ganglia, neuromuscular junctions, and all forms of muscle. The danger of such adverse reactions is proportional to the concentration of local anesthetic achieved in the circulation. In general, in local anesthetics with chiral centers, the -enantiomer is less toxic than the R-enantiomer. 

Are there any stereochemical requirements of local anesthetic compounds when they bind to the sodium channel receptors A number of clinically used local anesthetics do contain a chiral center (i.e., bupivacaine, etidocaine, mepivacaine, and prilocaine) (Table 16.2), but in contrast to cholinergic drugs, the effect of optical isomerism on isolated nerve preparations revealed a lack of stereospecificity. In a few cases (e.g., prilocaine, bupivacaine, and etidocaine), however, small differences in the total pharmacological profile of optical isomers have been noted when administered in vivo (41,42,43). Whether these differences result from differences in uptake, distribution, and metabolism or from direct binding to the receptor has not been determined. 

As an example of interesting applications of chiral GC, a few preparative scale separations must be mentioned. The large separation factors observed for the chiral inhalation anesthetic agents enflurane, isoflurane, and desflurane allowed preparative-scale separation of the enantiomers required for biomedical studies... 

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