Pharmacology enantioselectivity

These data clearly illustrate the enantioselectivity of the (-l-)-isomers of MDA, MDMA, and MBDB in producing an MDMA-like stimulus and underscore the fact that in vitro studies of the biochemical pharmacology of these substances should reveal similar selectivity, once the primary pharmacological process underlying the interoceptive cue is identified. The data also indicate that (-l-)-MDA is the most potent of all the drugs tested in MDMA- or in (-t)-MBDB-trained animals. The faet that (-l-)-MDA does not substitute in amphetamine-trained animals in our studies supports the argument that the pharmacology of this enantiomer of MDA is MDMA-like and is not like amphetamine. 

The enantioselective reduction of unsaturated alcohol derivatives has been applied to the synthesis of several biologically active compounds (Scheme 24.12). Warfarin (123, R=H) is an important anticoagulant that is normally prescribed as the racemate, despite the enantiomers having dissimilar pharmacological profiles. One of the earliest reported uses of DuPhos was in the development of a chiral switch for this bioactive molecule, facilitating the preparation of (R)- and (S)-warfarin [184]. Although attempted reduction of the parent hydroxycoumarin 122 (R=H) led to formation of an unreactive cyclic hemiketal, hydrogenation of the sodium salt proceeded smoothly with Rh-Et-DuPhos in 86-89% ee. 

The gas-phase guest-exchange reaction 29 has been employed to probe the enantioselectivity of permethylated /3-CD for pharmacologically important compounds, such as DOPA, amphetamine, ephedrine, and penicillamine (Scheme... 

Complex 2b also catalyzes the addition of imidazoles, benzimidazoles, and several purines to methyl allylic carbonates (Scheme 26) [76]. These reactions occurred with good yields and excellent enantioselectivities. -substituted heterocycles are found in a number of compounds that exhibit a range of biological activity. The syntheses of several pharmacologically active compounds were conducted with yields that were improved over those published previously. 

Racemic methadone (MET) is administered to heroin addicts as a substitution therapy. However, methadone enantiomers possess different pharmacological effects, and the drug has been demonstrated to be enantioselectively metabolized to its two major metabolites, 2-ethylidene-l,5-dimethyl-3,3-diphenylpyrrolidine (EDDP) and 2-ethyl-5-methyl-3,3-diphenyl-l-pyrroline (EMDP). Stereoselective separation of MET, EDDP, and EMDP using an alpha-glycoprotein stationary phase and MS-MS detection was proposed by Kelly et al. [34]. Optimal separation conditions were 20 mM acetic acid isopropanol (93 7, pH 7.4), with a flow rate of 0.9mL/min. 

The enzymatic enantioselective hydrolysis of esters of naproxen and ibuprofen has attracted considerable attention because the (S)-enantiomers of these nonsteroidal anti-inflammatory drugs (NSAIDs) are the pharmacologically active isomers. These reactions have been successfully performed in a range of ionic liquids (Figure 10.10) [60, 65, 121]. 

Enantiomeric purity, measured as the enantiomeric excess (ee) of an isomer, is determined by the formula (% major isomer)—(% minor isomer). Thus, if a chiral drag is said to be or 50% ee, the composite mixture contains 75% of one enantiomer and 25% of the other. Enantioselectivity refers to the greater activity of one enantiomer over its minor image. Enantiospecificily is rarely observed and implies that one enantiomer possesses 100% of the observed activity in most cases it is more accurate to use the term highly enantioselective. The pharmacologically more active enantiomer is termed the eulomei and the less active enantiomer is referred to as tire distomer. 

Ephedrine is the pharmacologically active enantiomers of ephe-drine. The enantiopurity tests for (-)-ephedrine can be performed using a peroctylated y-cyclodextrin based plastic membrane electrode [26], Bis (l-butylpentyl)adipate (BBPAP) was used as plasticizer and 10 3 mol/L NH4C1 as inner solution. The slope of the electrode is 60 mV/decade of concentration, and the potentiometric enantioselectivity coefficient is less than 10 4 The limit of detection is of 10 7 mol/L magnitude order. 

The discussed correlation between pharmacological profiles and absolute configurations needs little further comment. Qualitatively coherent enantioselectivities in the series generally support the dopaminergic character of the models. 

DNA is chiral by virtue of the asymmetric centers in the ribose units and as a result of the twist of the helix axis. Because of its inherent chirality, DNA is an attractive scaffold for enantioselection, which is of crucial importance in various fields such as drug and food analysis, biochemistry, or clinical pharmacology. Chaires et al. [116] reported a dramatic experiment demonstrating structural selectivity in DNA binding for the naturally occurring... 

Enantioselectivity of afDnity. If a receptor has sites for three of the substituents (symbolized in B by a cone, sphere, and cube) on the asymmetric carbon to attach to, only one Luellmann, Color Atlas of Pharmacology 2005 Thieme All rights reserved. Usage subject to terms and conditions of license. 

As more receptors are identified and isolated, the importance of RRA wiU likely increase, and they will be applied to enantiomer determination. As with enantioselective immunoassays, careful attention must be paid to the optical purity of standards and radioligands. The potential for interference by the inactive enantiomer should be considered. When possible, results should be obtained by use of a standard curve of the enantiomer and reported as concentration of the enantiomer. A disadvantage of RRA is its lack of ability to measure the pharmacologically inactive enantiomer, which may be important for toxicological reasons. The ability of RRA to... 

The issue of enantioselective efficacy and safety of salbutamol has been reviewed (1). Interest in chiral switch, that is the replacement of the racemic formulation by the pharmacologically active (i )-enantiomer levosalbutamol, may be hampered by enantiomeric interconversion in vivo and marked interindividual variation in salbutamol pharmacokinetics and pharmacodynamics, owing to complex interactions between genetic and environmental effects. The authors concluded that the advantage of levosalbutamol over the racemic formulation appears to be small with respect to efficacy and controversial with respect to safety. Two large crossover studies with multiple inhaled doses of (5 )-salbutamol in asthmatic patients showed no evidence of adverse effects on FEVi (2,3). 

The first examples of asymmetric Heck cyclizations that form quatemaiy carbon centers with high enantioselectivity came from our development of an asymmetric synthesis of the pharmacologically important alkaloid (—)-physostigmine (184) and congeners (Scheme 6-31) [68]. In the pivotal reaction, (Z)-2-butenanilide iodide 182 was cyclized with Pd-(5)-BINAP to provide oxindole 183 in 84% yield and 95% ee after hydrolysis of the intermediate silyl enol ether. With substrates of this type, cyclizations in the presence of halide scavengers took place with much lower enantioselectivity [68]. 

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