C CH33 459 OS 4aS l3bS butaclamn

Differential stereoselectivity has also been observed with agonists at the histamine receptor subtypes. The introduction of a methyl group a to the amino group in histamine results in the chiral molecule a-methylhistamine (4.60). Examination of the activity of the enantiomers of a-methylhistamine at the three histamine receptor subtypes yields eudismic ratios (R/S) of 1, 0.6 and approximately 100 at H1, H2 and H3 receptors respectively. The H1-receptor showing no stereoselectivity, the H2-receptor limited selectivity for the S-enantiomer and the H3-receptor showing marked stereoselectivity. Examination of pD2 values for the R-enantiomer at the three receptor subtypes yields values of 4.54, H1; 3.96, H2 and 8.40 at H3. Thus, R)-a-methylhistamine is a highly selective H3 agonist and stimulation at H3-receptors would be expected to occur at concentrations 104 times lower than those required for H1 or H2 stimulation. Similar stereoselectivity for the H3-receptor is also observed for a,P-dimemylhistamine. In this case the aR,pS-enantiomer (4.61) is 100 fold more active than its aS,pR-antipode and shows 130,000 fold greater selectivity for the H3 receptor than the other two subtypes. Compound (4.61) is the most active chiral agonist known at H3-receptors and shows the greatest receptor subtype selectivity. These two examples illustrate that the introduction of chirality into a critical site in a molecule may result in significant receptor subtype selectivity.

4.3.4 Quantitative structure—activity relationships

The significance of stereochemistry with respect to quantitative structure—activity relationships (QSAR) is dependent on the site of the chiral centre within the molecule. Is

Stereoisomers Acetylcholine

the chiral centre located in a position which will influence the interaction of the drug with the target receptor? A number of situations are possible:

(a) The chiral centre is located in a critical position within the molecule such that alteration of the stereochemistry, or structural modification to an achiral analogue results in a marked reduction in activity, e.g. the situation with (R)-adrenaline (4.31) referred to previously (p. 114).

(b) The chiral centre is located in a critical position within the molecule but the eutomer has enhanced, or the same activity, as an achiral analogue, the distomer being reduced in activity compared to the achiral compound. For example examination of the activity of the acetylcholine analogue (S)-fi-methacholine (4.62) on isolated rat intestine yields a pD2 value of 6.8, compared to the value of 7.0 obtained with acetylcholine, whereas, the Renantiomer, the distomer, yields a value of 4.1. In this case it appears that a two point interaction only is required for activity but that the orientation of the methyl group at the chiral centre is critical for activity. In the S-enantiomer, the eutomer, the methyl group is presumably orientated in a non-critical binding region of the receptor, whereas in the R-enantiomer the orientation results in steric repulsion.

(c) The chiral centre is in a non-critical position in the molecule such that both enantiomers and the achiral analogue have the same, or similar, activities. Examination of the properties of the H1-antihistamine terfenadine (4.63) in either pharmacological or biochemical assay systems, indicates no difference in activity between the enantiomers. Replacement of the hydroxy group at the chiral carbon atom by hydrogen yields an achiral derivative which has similar activity as the enantiomers of terfenadine. Thus the hydroxyl group is located in a non-critical position for receptor binding.

Critical Regions

If the chiral centre is located in a critical region of the molecule then differences in activity between isomers are expected and such differences would be greater for stereoisomers than for homologues, or analogues resulting from relatively simple isosteric replacements. To derive useful data from QSAR studies of chiral compounds each series of stereoisomers should be examined independently.

A useful approach for QSAR studies of stereoisomers in a related compound series is Eudismic Analysis, the eudismic index is plotted against the affinity, or potency, of the eutomer and the eudismic affinity quotient, the slope of the line, gives an indication of the stereoselectivity for a particular biological effect (Section 4.3.1). As a general rule the eudismic index is a function of the affinity of the eutomer, the higher the affinity of the drug the greater the degree of complementarity between the drug and its receptor site. Whereas for low affinity compounds the complementarity between the drug and receptor site will be lower and hence the eudismic index will be reduced. For drugs such as terfenadine, i.e. those in which the chirality is not critical for activity, a similarly low ratio would be expected.

The above relationship, the greater the affinity of the eutomer the greater the eudismic ratio, appears to be common for many series of drugs and is known as Pfeiffer's rule. Examples of compounds are known which do not follow this generalisation. In these cases: the chiral centre may be in a non-critical site in the molecule; two of the four groups attached to the chiral centre are bioisosteric and therefore, in biological terms at least, are not distinguished; the increased affinity of the distomers is due to additional interactions with the biomolecule which do not occur with the eutomer.


As many of the processes of drug absorption and disposition involve an interaction between the enantiomers of a drug and a chiral biological macromolecule it is hardly surprising that stereoselectivity is observed during these processes.

4.4.1 Absorption

The most important mechanism of drug absorption is passive diffusion through biological membranes a process which is dependent upon the physico-chemical properties of the molecule, e.g. lipid solubility, pKa, molecular size etc. If a chiral drug is absorbed by a passive process then differences between enantiomers would not be expected. However, differences between enantiomers may occur if the drug is a substrate for an active transport or carrier-mediated transport system. Such processes require the reversible combination of a substrate with a biological macromolecule and involve movement against a concentration gradient, expenditure of metabolic energy and may be saturated. Such systems show substrate specificity and hence would be expected to show stereoselectivity. Stereospecific transport systems are known to exist in the gastrointestinal tract for L-amino acids, dipeptides and D-carbohydrates etc. and drugs which are similar in structure to such naturally occurring substrates may be expected to be actively transported. Thus, L-dopa (4.64), L-penicillamine (4.65) and L-methotrexate (4.66) have been shown to be preferentially absorbed from the gastrointestinal tract compared to their D-antipodes which are not substrates and are absorbed by passive

diffusion. Such active processes may be expected, in theory at least, to increase the rate rather than the extent of absorption. In fact the bioavailability of D-methotrexate is only 2.5% that of the L-isomer.

Many of the P-lactam antibiotics are substrates for the gut dipeptide transport system and as such their absorption would be expected to be stereoselective. The influence of the stereochemistry of the 7-acyl side chain on the absorption of the diastereoisomers of cephalexin (4.36) has been investigated in the rat. Both diastereoisomers are substrates for the carrier mediated transport system with the L-epimer showing a higher affinity than, and acting as a competitive inhibitor for D-cephalexin transport. However, the L-epimer is also more susceptible to the intestinal wall peptidases and cannot be detected in serum, whereas the D-isomer is well absorbed. The drug is marketed as the single D-epimer.

Additional biochemical or pharmacological factors may also influence the stereoselectivity of drug absorption. For example the greater oral bioavailability of (-)-(Kj-terbutaline (4.67) compared to the less active (+)-5-enantiomer arises as a result of stereoselectivity in first pass metabolism and possibly due to the (-)-enantiomer increasing membrane permeability.

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