Distomers Of Dextropropoxyphene

where KEu and KDiS are equilibrium dissociation constants for the eutomer and distomer respectively. A plot of Eudismic Index versus pKEu, for a homologous or congeneric series of isomeric pairs of compounds generally yields a straight line. The slope of which is positive and is known as the Eudismic Affinity Quotient (EAQ) which is a quantitative measure of the stereoselectivity within the compound series for a particular biological effect.

It is important to appreciate that such terminology applies to a particular activity of a drug. For example in the case of a dual action drug the eutomer for one activity may be the distomer for another, or the enantiomers may be equal in activity. In the case of the P-blocking drug propranolol the eutomer for P-blocking activity is the enantiomer of the 5-absolute configuration, which is between 40 to 100 fold more potent than its antipode, depending on the test system used. In contrast the enantiomers of propranolol have similar activities with respect to their membrane stabilising properties. There are also examples where both enantiomers of a drug are marketed with different therapeutic indications. In the case of propoxyphene the dextrorotatory enantiomer of the 15, 2R-configuration is available as dextropropoxyphene (4.55) an analgesic agent and levopropoxyphene (4.56), with the 1R, 25-configuration, as an antitussive. In the case of this example not only are the molecules mirror image related but so are their trade names DARVON® (dextropropoxyphene) and NOVRAD® (levopropoxyphene).

4.3.2 "Purity" of enantiomerically pure drugs

The determination of the eudismic ratio of a pair of stereoisomers obviously depends on the availability of enantiomerically pure compounds. The reported eudismic ratios for the stereoisomers of a particular compound may vary widely within the literature. Whilst data of this type would be expected to vary from one laboratory to another an important contributory factor is probably associated with the enantiomeric purity of the materials examined particularly for the less active isomer. Early investigations on the activity of the enantiomers of chloroquine, for example, indicated that there were no differences in terms of toxicity or efficacy. Subsequent investigations have indicated that the "individual enantiomers" used in the initial study were little better than racemates. As the eudismic ratio increases then the significance of a small quantity of the eutomer as an impurity of the "inactive" distomer also increases. When isoprenaline was initially resolved the reported ratio of activities (R/S) was approximately 12. Further experimentation and improved resolution, in this case repeated fractional crystallisation, resulted in a 1000 fold difference in activity.

The influence of relatively small quantities of stereoisomeric impurities on eudismic ratio may be illustrated by a recent report of the activity of the stereoisomers of formoterol a p2-selective agonist. Formoterol (4.57) has two chiral centres and therefore exists in four stereoisomeric forms, the two chiral centres being positioned a and p to the aliphatic nitrogen atom. An examination of the activity of the four isomers on the relaxation of airway smooth muscle, indicated a relative order of potency of aR,pR>aS,pR^aS,pS> aR,pS. In an early report the eudismic ratio for the enantiomers aR, pR/aS, pS was determined to be 14. A more recent investigation reported the same relative order of isomeric potency but a eudismic ratio aR,pR/aS,pS of 50. In the later study the distomer, the aS,pS-enantiomer, was contaminated with 1.5% of the active aR,pR-isomer. Reduction in the "active impurity" to less than 0.1% resulted in an increase in eudismic ratio aR,pR/aS,pS to 850 and similar reductions of the "impurity" in the aS,pR-and aR,pS-stereoisomers resulted in an altered order of relative potency to aR,pR> aS,pR=aR,pS>aS,pS. Further increases in the "purity" of the inactive isomer may result in an increase in eudismic ratio.

The degree of enantiomeric purity is frequently not specified in the pharmacological literature, or alternatively, is presented in terms of optical rotation which is not a very sensitive technique at levels of contamination of a few percent. In such cases analytical methodology with an increased sensitivity for enantiomeric analysis is more appropriate, e.g. chromatographic methods using chiral stationary phases. The limitations of optical rotation determinations may be illustrated by a consideration of the BP 1993 monograph on naproxen. Naproxen (4.58) is a nonsteroidal anti-inflammatory drug marketed as the single dextrorotatory S-enantiomer. The BP requires the optical rotation of the material, determined in chloroform, to be between +63.0 and +68.5° which based upon the


published specific rotation corresponds to a stereochemical purity of between 95.5 to 103.7%. In comparison the analytical limits for purity determination by volumetric analysis are 98.5-100.5%. Thus, the chemical purity limits are more stringent than those for the stereochemical purity.

4.3.3 Receptor selectivity

As pointed out above eudismic ratios are only of significance for a particular biological activity of a drug. For a drug which can act at two or more sites differences in eudismic ratio provides useful information in terms of the stereochemical demands and geometry of the site, a means of comparison between receptors in different tissues and may also be used as a method of distinguishing receptor subtypes. Obviously such comparisons must be made with caution to ensure that potentially misleading factors, e.g. diffusion barriers, tissue uptake and metabolism, are taken into account or controlled as such factors may vary markedly between tissues.

The activity of the enantiomers of the neuroleptic agent butaclamol have been investigated with tissue preparations containing D2-dopaminergic, a-adrenergic, 5-HT2 and 5-HT1 serotoninergic, and opioid receptors. The eudismic ratio, (+)/(-), varied markedly with receptor system, (+)-(3S,4aS,13bS)-butaclamol (4.59) being 1250 times more active than the (-)-enantiomer in displacing haloperidol at D2-receptors, 143 times more active at displacing LSD at 5-HT2-receptors and equally active at displacing nalorphine at opioid receptors. The greater eudismic ratio was observed for actions in which the compound showed the greatest potency (see Section 4.3.4).

Comparison of the stereochemical discrimination of the enantiomers of noradrenaline by the a1 and a2-adrenergic receptors indicates basic differences between the two receptor subtypes. The eudismic ratios (R/S) obtained being 107 and 480 fold for a1 and a2 receptors respectively. Similar differences are also observed for a-methylnoradrenaline, the eudismic ratios for the 1R,2S/1S,2R enantiomeric pair being a1, 60 and a2, 550. Thus, for phenylethylamine derivatives the steric demands of the a2-receptor are more stringent than those of the a1-receptor subtype.

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