Enantiomers drug-receptor interactions

This view offers an explanation for the stereoselectivity of the phenylisopro-pylamines, i.e., the isomer that is more active is the one that presents least interference to the drug-receptor interaction. This idea would be consistent with the observation that the R enantiomers of the phenylisopropylamines have receptor affinity similar to their nonalpha-methylated homologs, and that the alpha-methyl of the S enantiomer of the amphetamines has a deleterious effect on affinity (72,78). There is no strongly compelling evidence in favor of either of the above hypotheses, however, and either is tenable. 

The SAR is also determined at the level of stereochemistry of interaction. In principle, three limiting situations can apply to the stereochemistry of drug-receptor interactions the enantiomers may not differ in activity the species may differ quantitatively or they may differ qualitatively. 

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. 

Figure 1 Easson-Stedman model of the drug-receptor interaction [17], The more active stereoisomer (top) is involved with three simultaneous complementary bonding interactions with the receptor active site, B—B, C—C and D—D its less active enantiomer (lower) may interact at two sites only irrespective of its orientation to the active site.

The most important differences between enantiomers occur in drug receptor interactions. Indeed, Lehmann [34] has stated, the stereoselectivity displayed by pharmacological systems constitutes the best evidence that receptors exist and that they incorporate concrete molecular entities as integral components of their active-sites. In contrast to the pharmacokinetic properties of a pair of enantiomers (Sec. 4), differences in pharmacodynamic activity tend to be more marked, and eudismic ratios of 100 to 1000 are not uncommon. 

As described for receptor interactions, enantioselectivity may also be manifested in drug interactions with enzymes and transport proteins. Enantiomers may display different affinities and reaction velocities. 

Admittedly, the separation of enantiomers is often difficult and expensive. However, now that we are in the 21st century, the need for optically active drugs capable of stereospecific interactions with drug receptors is a recognized prerequisite in drug design. 

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. 

A clear three-dimensional visualization of the means by which a receptor could differentiate between enantiomers was provided by Easson and Stedman in 1933 [25]. They proposed that three (b, c, d) of the four groups (a, b, c, d) linked to a chiral carbon atom were concerned in the process (either by normal valence forces, or by adsorptive or other forces). The receptor possessed three groups b, c and d for maximum physiological effect, the drug molecule must become attached to the receptor in such a manner that the groups b, c and d in the drug coincide respectively with b, c and d in the receptor. Such coincidence can only occur with one of the enantiomorphs and this consequently represents the more active form of the drug . The interaction (5) and non-interaction (6) were illustrated as follows ... 

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. 

It is very important to realise that when drugs or medicines are administered to the body there is the opportunity for chiral interactions. This is because the human body is composed of enzymes and receptors that are protein in nature. These proteins are polymers of 20 or so naturally occurring amino acids. With the exception of glycine, all of these amino acids are chiral (all are L-series amino acids - see later) and it must be expected that a chiral drug will interact with these chiral receptors differently from its enantiomer. It is often the case that if a racemic mixture of a chiral drug is administered, only one enantiomer will be active, while the other will be... 

Almost all drug-macro molecule interactions occurring in the body show chiral discrimination. This is true whether they are drug-enzyme or drug-receptor in nature. The situation is complicated further because some drugs show stereoselective absorption, distribution and excretion between enantiomers and it is difficult to determine which effects are due solely to metabolism and which are due to other biopharmaceutical factors. 

In addition to a reversal in potency, a dual-action drug may show equipotency for one activity. Carvedilol (Fig. 6) is a nonselective p-adrenoceptor antagonist with vasodilator activity used in the treatment of hypertension and angina. (iS)-Carvedilol is a potent competitive inhibitor at pi-adrenoceptors, whereas the 7 -enantiomer is considerably less potent, with pA2 values of 9.4 and 3.9 for (S)- and (7 )-carvedilol, respectively [39]. In contrast, the enantiomers are essentially equipotent with respect to ai-adrenoceptor blockade, with pA2 values of 7.87 and 7.79 for the S- and / -enantiomers, respectively [39]. Thus the vasodilator and antihypertensive effects of the drug arise as a result of ai-adrenoceptor blockade of both enantiomers and the pi-blockade from the -enantiomer which prevents reflex tachycardia. Similarly to amosulalol, outlined above, the lack of stereoselectivity with respect to ai-adrenoceptor blockade is presumably associated with the hydroxy group being located in a noncritical region of the molecule for receptor interaction. 

Figure 3 Enantiomers of chiral drugs show different biological properties. The monoterpenes (/ )- and (5)-limonene (9a, b) and (/ )- and (5)-carvone (10a, b) interact with the olfactory receptors (which are, like many drug receptors, G-protein-coupled receptors) in a different manner, producing different odors that are indicated under the individual formulas...

Natural molecules are almost invariably chiral, so all types of biological receptors—taste, odor, and drug receptors—are also chiral. This means that enantiomers interact differently with these receptors. For example, i -limonene, 7.59, is derived from citrus peel and has an odor of oranges. By contrast, 5-limonene is obtained from Douglas fir needle oil and smells of turpentine/pine. / Carvone, 7.60, has the odor of spearmint and is extracted from spearmint oil. S-Carvone is extracted from dill seeds and smells of caraway. Menthol, 7.61, is a... 

Section 7 8 Both enantiomers of the same substance are identical m most of then-physical properties The most prominent differences are biological ones such as taste and odor m which the substance interacts with a chiral receptor site m a living system Enantiomers also have important conse quences m medicine m which the two enantiomeric forms of a drug can have much different effects on a patient... 

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