Drug Receptor Binding: What is a stereoisomer and how does it relate to drug-receptor binding? What about enantiomers and racemic mixtures?
According to Wikipedia
are isomeric molecules that have the same molecular formula and sequence of bonded atoms (constitution), but which differ only in the three-dimensional orientations
of their atoms in space. Structural isomers share the same molecular formula, but the bond connections and/or their order between different atoms/groups differs. In stereoisomers, the order and bond connections of the constituent atoms remains the same, but their orientation in space differ."
· The stereochemistry of a receptor is constant
...something that cannot be manipulated. However, the drug can be changed. You can choose which drug, with a specific stereochemistry, to apply to the body.
- · Given the fact that chirality (stereoisomerism) is an
- extremely common phenomenon in nature and in biology, it is not surprising that most drugs are chiral (asymmetric). A number of chiral drugs that are used clinically are available/administered as racemic mixtures, ie, mixtures of ‘optical isomers’ or enantiomers (e.g., S- and R-ibuprofen, S- and R-warfarin, R- and S-verapamil), whereas the
- rest are marketed as a single active enantiomer.
, which are mirror images of each other
, contain one or more asymmetric centers and have opposite stereochemistry at all centers.
- · In most cases, one drug enantiomer is much more potent than the other, reflecting a better ‘fit’ to the receptor molecule.
For example, (-) ephedrine shows: 3 times more pressor activity than (+) ephedrine, 5 times more pressor activity than (+) pseudoephedrine, and 36 times more pressor activity than (-) pseudoephedrine.
Another example is (-) epinephrine which exhibits 12 to 15 times more vasoconstrictor activity than (+) epinephrine. Numerous other examples exist in the literature.
(Think of the receptor site as if it is a ‘glove’ into which the drug molecule must fit to bring about its effect !!)
· Another important outcome of drug chirality is that an active or a more active enantiomer/stereoisomer at one type of receptor site may not be active (or more active) at another type of receptor site
(e.g., a receptor type that may be responsible for some undesirable side effect), when compared to the other isomer.
- For example, the dextrorotatory isomers
- (the (+) enantiomers) in the morphine series of drugs, such as dextromethorphan, are cough suppressants that possess the anti-tussive
- properties of codeine (which has a levorotatory, (-), stereochemistry), without the analgesic, addictive, central depressant, and constipating features
- exhibited by the (-) form. The (+) form simply does not bind to the receptors involved in analgesic, constipative, addictive, and other actions exerted by the (-) form. As a result, dextromethorphan has largely replaced many older anti-tussives, including codeine, in prescription and nonprescription cough preparations.
- Another example is the local anesthetic levobupivacaine, which is the (S) isomer of bupivacaine. Bupivacaine is available on the market; it is the racemic mixture of the (R)
- and (S) isomers. Both the (R) and (S)
- isomers have good local anesthetic activity, but the (R) isomer causes myocardial depression and ventricular arrhythmias. In contrast, the (S) isomer shows much less cardio-toxicity. Consequently, the
- pure (S) isomer of bupivacaine is now available on the market because of its superior safety profile.
- · A number of drugs are available/marketed as racemic mixtures (a racemic mixture is
- a 50:50 mixture of the (-) and (+) enantiomers).
- In some cases, unfortunately, the patient is receiving drug doses of which 50% is either inactive or toxic. As a result, there is a great deal of interest, at both the FDA and the pharmaceutical industry, in making more chiral drugs available as
- their pure active enantiomers.
- · As dramatic as the above examples of stereoselectivity may be, sometimes it may not be
- cost-effective to resolve the drug into its pure enantiomers. In some cases, it is difficult to conclude that one isomer of a drug is superior to
- the other.
- For example, S-verapamil is a more active calcium channel blocker than R-verapamil, but the former is more rapidly metabolized by the first-pass effect in the liver; this means that R-verapamil has a much
- higher bioavailability than the more active S
- isomer (which of the two isomers is clinically superior ??).
In other cases, it makes little difference whether a racemic mixture or a single pure isomer is administered because of the biotransformation (metabolic) reactions
that a drug molecule is subjected to in the body.
- For example, the NSAID ibuprofen is sold as the
- racemic mixture. S-ibuprofen is the active anti-inflammatory isomer (inhibitor of cyclooxygenase). The R isomer, on the other hand, has centrally acting analgesic activity, but it is converted metabolically to the S isomer in vivo.