R-antipodes. R)-11-Hydroxy-10-methylaporphine (4.92) is a highly selective 5-HT1A agonist, whereas its S-antipode (4.92) is an antagonist at the same receptor. Similarly, (S)-apomorphine (4.93) acts as an antagonist at dopaminergic receptors (D1 and D2) whereas the R-enantiomer is an agonist. In the case of 11-hydroxyaporphine the Renantiomer activates dopamine receptors and the S-enantiomer is an antagonist.

A similar though more complex situation arises with 3-(3-hydroxyphenyl)-N-propylpiperidine (3-PPP; 4.94). The initial pharmacological evaluation of this compound was carried out using the racemate and 3-PPP was described as a highly selective presynaptic dopaminergic agonist. Resolution and pharmacological evaluation of the individual enantiomers indicated that the situation was more complex. ^-3-PPP acts as an agonist at both pre- and postsynaptic dopamine receptors, whereas (5^-3-PPP stimulates presynaptic and blocks postsynaptic receptors. The pharmacological profile observed with the racemate arises from the sum of the activities of the individual enantiomers. (5^-3-PPP has been selected for further evaluation as it appears to influence dopaminergic function in two different ways, i.e. stimulation of the pre- and blockade of the postsynaptic receptors.

The 1,4-dihydropyridines are calcium-channel blockers used for the treatment of angina and hypertension. A number of these agents possess a chiral centre at the 4-position of the dihydropyridine ring system and a number of examples are known in which the enantiomers have opposing actions on channel function, e.g. compounds (4.95), (4.96) and (4.97). The S-enantiomers act as potent activators, whereas the Renantiomers are antagonists at L-type voltage-dependent calcium channels. It was thought that the observed effects of the enantiomers of these agents were due to

(4.95} (4.%) (4.97)

interactions at different binding sites. However, it appears that the enantiomers interact with different channel states, open and inactivated, the drug binding sites of which have opposite steric requirements. The situation is further complicated as the S-enantiomers of (4.95) and (4.97) are activators at polarised membrane potentials but become antagonists under depolarising conditions. Indeed one author has described these agents as being "molecular chameleons".

4.5.5 One enantiomer may antagonise the side effects of the other

Indacrinone (4.98), a rn-indanyloxyacetic acid derivative, is a loop diuretic with uricosuric activity, which has been evaluated for the treatment of hypertension and congestive heart failure. However, following administration of the racemate to man serum urate levels increase. Resolution and pharmacological evaluation of the individual enantiomers indicates that the diuretic and natriuretic activity reside in the (-)-^-enantiomer (4.98) and the uricosuric effects reside in (+)-(SMndacrinone (4.98). Following administration of the racemate to man the plasma half-life of the S-

enantiomer ( ^'compared to the R, l^-l-h) and hence its uricosuric activity is too short to prevent the increase in serum uric acid. Alteration of the enantiomeric composition of the drug from the 1:1 ratio of the racemate by increasing the proportion of the (+)-S-enantiomer resulted in a mixture (S;^:4:1) which was isouricemic and a further increase (S;^:8:1) resulted in a mixture which caused hypouricemia. Hence, in the case of indacrinone the evaluation of the differences in both the pharmacodynamic and pharmacokinetic properties of the individual enantiomers and subsequent manipulation of the enantiomeric composition of the drug results in an improved therapeutic profile.

(4.98); {S) - indacrinone (4.IJS ); W - indat rinoni;

4.5.6 The required activity resides in one or both enantiomers but the adverse effects are predominantly associated with one enantiomer

Ketamine (4.99) is a general anaesthetic agent with analgesic properties which does not cause circulatory or respiratory depression. However, its use is restricted by post-anaesthesia reactions including hallucinations and agitation; the drug is also the subject of abuse. Both enantiomers have anaesthetic properties but (+)-(S)-ketamine is between three to four fold more potent than the A-enantiomer and has approximately twice the affinity for the opiate receptor. The incidence of the adverse effects, the so-called "emergence reactions", reported for the drug are greater following the administration of the A-enantiomer than either the racemate or (S^-ketamine. From the available information it would appear that the development of the single enantiomer would be therapeutically beneficial and also reduce the abuse potential of the drug.

(4.99); ketamine


As pointed out previously the problems associated with drug stereochemistry are not restricted to particular groups of agents but extend across all therapeutic groups. In this section the stereochemistry of some selected therapeutic agents will be examined in an attempt to illustrate some of the complexities which may arise. This is not intended to be an exhaustive compilation but merely to serve as an indication of the potential advantages of stereochemical considerations in pharmacology.

4.6.1 Antiarrhythmic Agents


Verapamil (4.100) is a calcium channel blocking agent used for the treatment of supraventricular tachyarrhythmias, hypertension and angina. The pharmacodynamic activity of the enantiomers varies quantitatively, with the S-enantiomer being 2.5 to 20

fold more potent than (^-verapamil in terms of vasodilation and negative inotropic, dromotropic and chronotropic effects depending on the test system used. An examination of the pharmacological properties of the drug in vivo are also complicated by the formation of norverapamil (the N-desmethyl metabolite) an active metabolite which is reported to have ca 20% of the vasodilation activity of the drug.

Verapamil undergoes extensive first-pass, or presystemic metabolism, and based on "total" drug concentrations has a bioavailability of between 20-30%. Examination of the plasma concentration effect relationship, by measurement of the PR interval prolongation following both oral and intravenous administration of the racemic drug indicates that the drug is apparently more potent following intravenous administration. A three fold greater plasma concentration being required following oral administration to produce the same pharmacodynamic effect, i.e. a shift in the dose response curve to the right is observed following oral drug administration. This difference in potency with route of administration is however only apparent and arises due to the differential oral bioavailability of the individual enantiomers of verapamil. Following intravenous administration the plasma concentrations of the less active R-enantiomer are twice those of the active S-enantiomer, whereas following oral administration this ratio R/S is ca 5. This difference in plasma concentration arises as a result of the differential bioavailabilities of the individual enantiomers (R, -50%; S, -20%), the higher clearance of (^-verapamil (RS-0.57), and the higher volume of distribution of the S-enantiomer (R/S-0.4). The terminal half-lives of the two enantiomers are similar, between 4-5 hours, but not identical. Thus, an investigation of the stereochemical aspects of verapamil disposition explains the apparent anomaly in the concentration-effect relationship with route of administration.

In addition to its use in cardiovascular disease verapamil also has a potential application in the treatment of multidrug resistant tumours. In vitro studies with multidrug resistant tumour cell lines have indicated that verapamil enhances the cytotoxicity of the vinca alkaloids and anthracycline cytostatics, and reverses the resistance to these agents. One mechanism of multidrug resistance is due to a decreased accumulation of the cytotoxic agents as a result of the increased expression of P-glycoprotein (P-170) a membrane transport protein drug efflux pump. Verapamil inhibits this efflux pump by inhibiting the binding of cytotoxic agents and increases the intracellular content of vinblastine and related agents. Studies in vivo have however, been disappointing as the plasma concentrations of the drug required to enhance cytotoxicity cannot be achieved due to the cardiovascular effects of the drug. However, while the activity of (S)-verapamil is greater than that of the R-enantiomer in terms of the cardiovascular effects, both enantiomers have similar effects in terms of their inhibition of the membrane transport pump. It therefore follows that (R)-verapamil may be potentially useful as a single isomer drug as higher doses may be used, compared to the racemate, with a reduction in the cardiovascular effects.


Disopyramide (4.101) is used, as the racemate, in the treatment of ventricular and atrial arrhythmias and has anticholinergic effects, common side effects include dry mouth and urinary retention. The use of the drug is limited since it reduces cardiac output and left ventricular performance. The antiarrhythmic activity appears to reside predominantly in the enantiomer of the S-configuration, as determined by prolongation of electrocardiogram

(4.101); (5) - disopyramide (4.101); (tf) - disopyramide

QT interval which is between 4 to 5 fold longer following the S- than the Renantiomer. The S-enantiomer is also four to five fold more potent in terms of the anticholinergic activity. There are also pharmacokinetic complications with disopyramide as following the individual administration of the enantiomers to man there are no significant differences in the total clearance, renal clearance or volume of distribution. However, on administration of the racemic mixture (^-disopyramide has a lower total clearance, renal clearance, volume of distribution and shorter plasma half-life compared to the R-enantiomer. These differences in pharmacokinetics, following administration of the individual enantiomers and the racemate, arise due to enantiomer-enantiomer interactions in plasma protein binding which is also concentration dependent.


Tocainide (4.102) is an orally active antiarrhythmic agent developed from lignocaine. The drug is used as a racemate but the R-enantiomer has three times the activity of (S)-tocainide in a chloroform induced model of fibrillation in the mouse. The plasma half-life of the i?-enantiomer at approximately 10 hours is shorter than that of (S)-tocainide (t,„ Li~17 hours>wilh the result that following an intravenous infusion of the drug the ratio of enantiomers (S/R) in plasma increases from ca 1 at 2 min to ca 1.7 after 48 hours. Hence "total" drug plasma concentrations will increase progressively during the infusion but with relatively small changes in pharmacological effect. There is also considerable interpatient variability in the enantiomeric composition of the material in plasma, the S/R ratio varying between 1.3 to 3.8, which is probably associated with variability in metabolism.

4.6.2 P-Blockers

The P-adrenoreceptor antagonists may be divided into two chemical groups the arylethanolamine and aryloxypropanolamine derivatives. These agents show a high degree of stereoselectivity with respect to their action at the P-receptor with the pharmacological activity residing in the enantiomers of the ^-configuration of the arylethanolamine series and the 5-enantiomers of the aryloxypropanolamine group. Examination of the general structures of the active enantiomers of the two series, (4.38) and (4.39), indicates that the three-dimensional spatial arrangement of the active enantiomers are identical inspite of their opposite configurational designations. The stereoselectivity exhibited by these agents may vary markedly, the eudismic ratio for the binding affinity of atenolol enantiomers to the P-receptor being as low as 10 whereas that for pindolol is 1000. Differences in eudismic ratio between P-receptor subtypes have also been observed which indicate that P1-receptors are more sterically demanding than P2-receptors, i.e. higher endismic ratios are observed at P1-receptors than at the P2-subtype. This should not be surprising as there are known to be structural differences between the receptor subtypes. A recent QSAR study has indicated that the differences in enantiomer binding affinity between the two receptor subtypes is associated with higher equilibrium dissociation constants for the distomers at the P2-receptor subtype compared with the P1-subtype. An additional physico-chemical property of significance in determining the binding affinity of these agents is their lipophilicity. The addition of the lipophilicity parameter (log P) to the QSAR correlation equations indicated that hydrophobic parameters are of greater significance for drug binding to the p2-receptor than the p1, particularly for the less active distomers for which the binding "fit" would obviously not be expected to be as good as for the eutomers. Thus the "steric" differences observed between the receptor subtypes may arise as a result of increased binding of the distomers to the p2-receptor via hydrophobic interactions.

For those P-blockers which show additional pharmacological properties, e.g. the membrane stabilising effects, the enantiomers appear to be equipotent (see below).

Of the P-blockers currently available only two, timolol (4.103) and penbutolol (4.104), are marketed as single isomers and being of the aryloxypropanolamine series these agents are available as the S-enantiomers. The remainder are marketed as racemates and in the case of one compound, labetalol (see below), as a mixture of four stereoisomeric forms. In terms of their use in the treatment of hypertension and angina there appears to be relatively little advantage in using single enantiomers particularly as the majority of the adverse effects are related to their pharmacological action and therefore a significant

reduction in side effects is unlikely. There are however a number of reasons why the stereochemistry of the P-blockers should not be neglected as indicated in the examples cited below.

Propranolol (4.105) is a lipophilic non-selective P-blocker marketed as a racemate, the S-enantiomer being between 40 to 100 times, depending on the test system used, more potent as a P-blocker than the R-enantiomer. The enantiomers show no differences in activity with respect to the membrane stabilising properties of the drug.

Following administration of racemic propranolol to man an examination of plasma concentration effect relationships, based on "total" drug concentrations, results in a shift in the dose response curve with route of administration. The drug appears to be between two to three fold more potent following oral dosing than following intravenous administration (the opposite to that observed with verapamil, Section 4.6.1). Propranolol undergoes extensive first-pass, or presystemic, hepatic metabolism which is stereoselective for the less active R-enantiomer, thus the apparent greater potency based on "total" plasma concentrations is a reflection of the increased proportion of the S-enantiomer in the circulating material. Following oral administration of the drug the enantiomeric composition of the material in plasma (S/R) varies between 1 to 4 fold. An additional contributory factor to the increased drug potency following oral compared to iv administration may be the higher plasma concentrations of the active metabolite 4-hydroxypropranolol (4.108).

The metabolism and excretion of the enantiomers of propranolol have been examined in some detail. Three main pathways are involved, glucuronidation of the side chain hydroxyl group (4.106), oxidative metabolism of the aliphatic side chain to yield 3-naphthyloxylactic acid (4.107) and aromatic oxidation to 4-hydroxypropranolol (4.108), which may undergo glucuronidation and sulphation. Each of these pathways may exhibit stereoselectivity and an examination of the urinary metabolites indicates that aromatic oxidation is selective for R)-propranolol whereas side chain oxidation and glucuronidation are selective for the S-enantiomer (Table 4.4). However, the situation is slightly more complex and examination of the drug enantiomer clearance and partial metabolic clearance indicates that the metabolism of propranolol is dominated by aromatic oxidation to yield the 4-hydroxy compound, which is highly selective for the R-enantiomer; the partial metabolic clearance via the alternative pathways showing only slight stereoselectivity (Table 4.4). Thus, the enantiomeric composition of the urinary excretion products reflects the increased concentrations of (S)-propranolol available to undergo these transformations.

(4.]<kt> OH (4.107)
Oil (4.I0K)

G " glucuronic acid

Table 4.4 Fate of propranolol enantiomers in man.

G " glucuronic acid

Table 4.4 Fate of propranolol enantiomers in man.

Urinary recovery

Clearance and partial

(% dose)

metabolic clearance




s S/R


0.16 0.24 1.50


1.96+ 0.71

Propranolol glucuronide

5.4 9.6 1.76


0.27 1.1

Naphthoxylactic acid

7.9 11.5 1.45


0.31 0.82


19.5 11.6 0.59


0.35+ 0.40

* Total of conjugated material, i.e. both glucuronide and sulphate conjugates, both conjugation reactions may also exhibit stereoselectivity. + Significantly different for the two enantiomers of propranolol.

* Total of conjugated material, i.e. both glucuronide and sulphate conjugates, both conjugation reactions may also exhibit stereoselectivity. + Significantly different for the two enantiomers of propranolol.

As pointed out above timolol (4.103) is one of the few P-blockers presently available as a single enantiomer. In addition to its use in the treatment of hypertension and angina timolol is also used for the treatment of wide angle glaucoma. Following administration to the eye significant amounts of the drug are systemically absorbed and cardiovascular and pulmonary side effects have been reported. This systemic absorption is of particular significance for the use of the drug in patients for whom P-blocking agents are contraindicated, e.g. those with respiratory disease states, and a number of deaths have been reported following the use of timolol eye drops in asthmatic patients.

Using pharmacological test systems for the evaluation of P-blockade (S)-timolol shows marked stereoselectivity in action with eudismic ratios (S/R) of between 50 and 90 depending on the test system used. These large differences in activity reduce to ca three fold when the ocular properties of the drug are examined, e.g. reduction in aqueous humour recovery rate, inhibition of dihydroalprenolol binding in the iris-ciliary body. The R-enantiomer of timolol has also been shown to reduce intraocular pressure in patients with glaucoma with fewer systemic effects than (S)-timolol. In addition, recent investigations have indicated that R)-timolol increases retinal/choroidal blood flow, whereas the S-enantiomer decreases it, an unrequired effect. The stereoisomers of timolol therefore represent a possible example of a drug where both enantiomers could be marketed for specific therapeutic indications, the S-enantiomer for the treatment of cardiovascular disease states and the R-enantiomer for the treatment of glaucoma.

Sotalol (4.109), an arylethanolamine derivative, is a non-selective P-blocker used as a racemate the (-)-enantiomer being 14-50 fold more active, depending on the test system used, than (+)-sotalol in terms of P-blockade. Racemic sotalol also has antiarrhythmic activity, prolonging the duration of the cardiac action potential and increasing ventricular repolarisation time. In terms of antiarrhythmic activity both enantiomers appear to be equipotent and it has been suggested that the single (+)-enantiomer may have potential as an antiarrhythmic agent devoid of P-blocking activity.

Labetalol (4.110, see Table 4.5), an arylethanolamine derivative, is a dual action drug with combined a and P-blocking activity. Labetalol contains two chiral centres and is marketed as an equal parts mixture of all four possible stereoisomers. Examination of the pharmacological activity (pA2 values) of the four possible stereoisomers (Table 4.5), indicates the P-blocking activity resides in the R,R-stereoisomer, the a1-blocking activity in the S,R-stereoisomer and that the remaining pair are essentially inactive. Labetalol is certainly not one drug with two actions. The R,R-stereoisomer of labetalol, named dilevalol, has been investigated for development as a single isomer P-blocker. However, the development of this compound was stopped following clinical trials in which a small number of patients developed drug induced hepatitis. This adverse effect appears to be of minor significance with respect to labetolol and the reason why the single isomer should


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