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STEREOISOMERS AND STEREOGENICITY OF
SOME CHIRAL ORGANIC COMPOUNDS AND ITS
EFFECT AS MEDICINAL DRUG.
A TERM PAPER
DR.SAMUEL OSAFO ACQUAH
IN FULFILLMENT OF THE REQUIREMENT OF THE COURSE
DESMOND BOATENG OFOSU
(BSc. CHEMISTRY-THIRD YEAR)
KWAME NKRUMAH UNIVERSITY OF SCIENCE AND TECHNOLOGY
DEPARTMENT OF CHEMISTRY
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TABLE OF CONTENTS
TYPES OF STEREOISOMERS ………………………………………………………………………..8
5. CHIRALITY OF ORGANICCOMPOUND…………………………………………………………….11
CHIRAL DRUGS AND THEIREFFECTS……………………………………………………………13
IMPORTANCE OF CHIRALDRUGS……………………………………………………………14-16
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The importance of stereochemistry in drug action is gaining greater attention in medical practice, and a
basic knowledge of the subject will be necessary for clinicians to make informed decisions regarding the
use of single-enantiomer drugs over the racemic form. Many of the drugs currently used are in mixtures of
enantiomers. For some therapeutics, single-enantiomer formulations can provide greater selectivities for
their biological targets, improved therapeutic indices, and/or better pharmacokinetics than a mixture of
enantiomers. This article reviews the effects of enantiomeric properties on some chiral organic compounds
as a result of their stereogenicity and stereoisomers, thus emphasizing on the potential biological and
pharmacologic differences between the 2 enantiomers of a drug. In some cases, both a mixture of
enantiomers and a single-enantiomer formulation of a drug will be available simultaneously. In these cases,
familiarity with stereochemistry and its pharmacologic implications will aid the practicing physician to
provide optimal pharmacotherapy to his or her patients.
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Stereochemistry, a sub-discipline of chemistry, involves the study of the relative spatial arrangement of
atoms within molecules. Stereochemistry is also known as 3D chemistry because the prefix "stereo-" means
"three-dimensionality".The study of stereochemistry focuses on stereoisomers and spans the entire
spectrum of organic, inorganic, biological, physical and especially supramolecular chemistry.
Stereochemistry includes methods for determining and describing these relationships; the effect on the
physical or biological properties these relationships impart upon the molecules in question, and the manner
in which these relationships influence the reactivity of the molecules in question (dynamic
stereochemistry). A basic concept of stereochemistry that is important to understand is that of chirality. Put
simply, chiral objects whether they are microscopic molecules or macroscopic objects are - irregularly
shaped (asymmetric) and are non-superimposable on its mirror image. Chirality exists all around us. For
example – a spiral staircase, a shoe, a tree, etc. are all chiral objects. Human hands are perhaps the most
universally recognized example of chirality: The left hand is a non-superimposable mirror image of the
right hand; no matter how the two hands are oriented, it is impossible for all the major features of both
hands to coincide. Therefore, the right hand is said to be chiral as well as the left hand.
In molecules; the understanding of chirality is important because biological molecules are often chiral.
Natural compounds such as - DNA, proteins, carbohydrates, lipids, steroids, etc. are chiral molecules.
Meaning, they have very irregular shapes (asymmetric) which make each one a unique individual
molecule. Making them uniquely qualified to interact and communicate with other unique individual chiral
molecules. Chiral molecules will only recognize and interact with molecules that have a certain
stereochemistry. Hence, any substances created by man to interact with or modify nature are interacting
with a chiral environment.
Additionally, the feature that is most often the cause of chirality in molecules is the presence of an
asymmetric carbon atom, which is referred to as a chiral center (chiral carbon) or stereo center
(stereogenic). A chiral center is a carbon atom bearing 4 different atoms or groups of atoms. Proteins are
often enantioselective towards their binding partners. When designing small molecules to interact with
these targets, one should consider stereoselectivity. As considerations for exploring structure space evolve,
chirality is increasingly important. Binding affinity for a chiral drug can differ for diastereomers and
between enantiomers. For the virtual screening and computational design stage of drug development, this
problem can be compounded by incomplete stereochemical information in structure libraries leading to a
"coin toss" as to whether or not the "ideal" chiral structure is present. Creating every stereoisomer for each
chiral compound in a structure library leads to an exponential increase in the number of structures resulting
in potentially unmanageable file sizes and screening times. Therefore, only key chiral structures,
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enantiomeric pairs based on relative stereochemistry need be included, and lead to a compromise between
exploration of chemical space and maintaining manageable libraries. In clinical environments, enantiomers
of chiral drugs can have reduced, no, or even deleterious effects. This underscores the need to avoid
mixtures of compounds and focus on chiral synthesis. Governmental regulations emphasizing the need to
monitor chirality in drug development have increased. The United States Food and Drug Administration
issued guidelines and policies in 1992 concerning the development of chiral compounds. These guidelines
require that absolute stereochemistry be known for compounds with chiral centers and that this information
should be established early in drug development in order that the analysis can be considered valid. From
exploration of structure space to governmental regulations it is clear that the question of chirality in drug
design is of vital importance. Over the last several decades scientist have become more aware of the
principle that much of nature/biology is chiral. And more importantly that nature is having to interact more
and more with a manufactured synthetic world of chemicals. Chemicals which may or may not have the
proper chiral configuration and thus the desired biochemical response. This is especially obvious in the
pharmaceutical industry and in the development of new drugs. In the manufacturing of pharmaceuticals,
often only one enantiomer of a racemic drug is the effective agent and has a therapeutically useful action.
While the second enantiomer does not have the desired therapeutic affect and may actually have an adverse
toxic effect (serious side effects). As a result, legislation now requires both enantiomers of a racemic drug
to be pharmacologically investigated. The three-dimensional structure of a molecule determines its physical
properties, such as the temperature at which it turns from a liquid to a gas (boiling point) and the
temperature at which it changes from a solid to a liquid (melting point). The geometric structure of a
molecule is also responsible for its chemical properties, such as its strength as an acid or base. The
compound trans-1,2-dichloroethene Illustration by Hans & Cassidy. Courtesy of Gale Group. becomes a
gas at a much higher temperature than the structurally similar cis-1,2-dichloroethene. The compound cis-3-
phenylpropenoic acid is a stronger acid than trans-3-phenylpropenoic acid only because the hydrogen
atoms are connected to the doubly bonded carbon atoms differently.
The geometric structure of a molecule can also have a dramatic effect on how that molecule tastes or how it
functions as a drug. The antibacterial drug chloramphenicol is commercially produced as a mixture of the
two compounds in Figure 5. One three-dimensional arrangement of atoms is an active drug, the other
geometric structure is ineffective as an antibacterial agent.
In most cases the energy of a molecule or a compound, that is, the particular energy level of its electrons
depends upon the relative geometry of the atoms comprising the molecule or compound. Nuclear geometry
means the geometrical or spatial relationships between the nucleus of the atoms in a compound or molecule
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(e.g., the balls in a ball and stick model). When a molecule or compound's energy is related to its shape this
is termed a stereoelectronic property.
Stereoelectronic effects arise from the different alignment of electronic orbitals with different arrangements
of nuclear geometry. It is possible to control the rate or products of some chemical reactions by controlling
the stereoelectronic properties of the reactants.
The importance of stereochemistry in biological systems extends to more than just drugs: our bodies, for
example, can only create and digest carbohydrates and amino acids of a certain stereochemistry. Thus, all
of our proteins that make up our hair, skin, organs, brain, and tissues, are composed of a single
stereoisomer of amino acids. Additionally, our bodies can make and digest starch (found in potatoes and
bread) but not cellulose (found in wood and plant fibers), even though both are just polymers of glucose of
different stereochemistry. These are just a few of numerous examples of the important role stereochemistry
plays in our everyday lives.
An asymmetric synthesis can also be achieved by applying a chiral catalyst. The catalyst can be an enzyme,
or a synthetic catalyst, usually one such as a chiral transition-metal catalyst. Catalytic asymmetric
syntheses are usually more cost-effective, though the enzymes and chiral transition-metal catalysts are
often more expensive than chiral auxiliaries or reagents, because they have to be applied in small, catalytic
quantities instead of stoichiometric amounts. Therefore, an additional advantage of catalytic processes is
that the disposal of byproducts poses less of an environmental impact. However, a disadvantage is the
toxicity of transition metals.
In industrial asymmetric syntheses, more and more transition-metal catalysts with chiral ligands are
applied. A well-known example of an asymmetric synthesis used in a large-scale production is the
Monsanto process for the manufacture of L-DOPA (L-dihydroxyphenylalanine). This proved useful in the
treatment of Parkinson's disease. In one catalytical step of this asymmetric synthesis, a chiral rhodium
catalyst is applied to a stereoselective hydrogenation of a double bond.
In the reaction with chiral reaction partners or chiral catalysts, enantiomers display different reaction rates.
If the difference is large enough, the enantiomers can be separated by stereoselectively converting only one
of the enantiomers, while the desired enantiomer remains. Since this is based on different reaction rates, the
separation technique is called kinetic resolution. A special case of kinetic resolution is the biochemical
resolution of racemates by stereoselective enzymic conversion of one enantiomer.
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WHAT ARE STEREOISOMERS
Stereoisomers are compounds that have identical sets of atoms configured in the same positions but are
arranged differently spatially. Stereoisomers are isomeric molecules that have the same molecular formula
and sequence of bonded atoms (constitution), but that differ only in the three-dimensional orientations of
their atoms in space. This contrasts with structural isomers, which share the same molecular formula, but
the bond connections or their order differs. By definition, molecules that are stereoisomers of each other
represent the same structural isomer. For example, in the case of the C4H8 hydrocarbons, most of the
isomers are constitutional. Shorthand structures for four of these isomers are shown below with their
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Note that the twelve atoms that make up these isomers are connected or bonded in very different ways. As
is true for all constitutional isomers, each different compound has a different IUPAC name. Furthermore,
the molecular formula provides information about some of the structural features that must be present in
the isomers. Since the formula C4H8 has two fewer hydrogens than the four-carbon alkane butane (C4H10),
all the isomers having this composition must incorporate either a ring or a double bond. A fifth possible
isomer of formula C4H8 is CH3CH=CHCH3. This would be named 2-butene according to the IUPAC rules;
however, a close inspection of this molecule indicates it has two possible structures. These isomers may be
isolated as distinct compounds, having characteristic and different properties. They are shown here with the
designations cis and trans.
The bonding patterns of the atoms in these two isomers are essentially equivalent, the only difference being
the relative orientation or configuration of the two methyl groups (and the two associated hydrogen atoms)
about the double bond. In the cis isomer the methyl groups are on the same side; whereas they are on
opposite sides in the trans isomer. Isomers that differ only in the spatial orientation of their component
atoms are called stereoisomers. Stereoisomers always require that an additional nomenclature prefix be
added to the IUPAC name in order to indicate their spatial orientation, for example, cis (Latin, meaning on
this side) and trans (Latin, meaning across) in the 2-butene case.
In contrast, isomers which differ in their connectivity but with the same molecular formula have bonded
(connected) together in different orders are called constitutional isomers. They have the same parts, but the
parts are connected to each other differently. Examples of isomers pairs which are consitutional isomers are
(1)butane and methylpropane,i.e., isobutane, which are different in that butane has a sequence of four
carbon atoms in a row, but isobutane has a three carbon chain with a branch (2)dimethyl ether and ethanol--
the former has a C-O-C chain, while the latter has a C-C-O chain (3) 1-pentene and cyclopentane--the
former has an acylic chain of 5 carbons, while the latter has a 5-membered ring.
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TYPES OF STEREOISOMERS
The are two main types of stereoisomers; namely enantiomers and diastereoisomers.
a. Diastereomers - occurs when two or more stereoisomers of a compound have different configurations
and are NOT mirror images of each other. Diastereomers have different physical properties (i.e. melting
point, boiling points, solubility, etc.).
b. Enantiomers - are two stereoisomers that are mirror images of each other that are “non-superimposable”
(like one’s hands). Enantiomers have exactly the same physical properties and the same chemical
properties. However, when they act in a chiral environment (i.e. the human body) they exhibit a different
physiological activity (i.e. odor, receptor binding, pharmacological effect).
Since two enantiomers are mirror images of each other, they are not distinguished by any physical or
chemical means which cannot distinguish mirror images, i.e., which are not themselves chiral (handed,
meaning can distinguish left from right). Therefore 2 enantiomers have exactly the same energy, solubility
in typical achiral solvents, boiling and melting points, NMR and IR spectra, etc. Their chemical properties,
including both the qualitative reactions and the quantitative rates of reaction are identical when reacting
with achiral chemical species. In general, then, both chemical and physical properties of 2 enantiomers
are exactly identical twoard achiral agents,chemical or physical. ,li>It is important to realize, however,
that when 2 enantiome4s react with a pure single enantiomer of another chiral compound, the rates of
reaction of the 2 enantiomers will be different (more later). Also, one physical property which can
distinguish them is "optical activity" (see below).
Diastereoisomers are not mirror image isomers. They are essentially like any other pair of isomers (e.g.,
constitutional isomers) in that they have distinct chemical and physical properties. Since they have the
same functional groups, however, they are usually rather similar to one another in their reactions and
properties. Two diastereoisomers can usually be separated from one another by , e.g., recrystallization,
since they have different solubilities.
Although their chemical properties(reactions) are similar, the two diastereoisomers will typically react at
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STEREOGENICITY OF ORGANIC COMPOUND
A stereocenter or stereogenic center is an atom bearing groups such that an interchanging of any two
groups leads to a stereoisomer. The most common stereocenters are chiral centers (such as asymmetric
carbon atoms) and the double-bonded carbon atoms in cis-trans alkenes. If a molecule has a single
stereogenic center it will necessarily be chiral. The most common kind of stereogenic center is a carbon (or
other atom) which has four different atoms or groups directly attached to it. You can see that the
central carbon of 2-butanol (the one marked by an asterisk) is a stereogenic center, having H,OH,methyl,
and ethyl groups attached. Since it has just a single stereogenic center , it must be chiral. On the other
hand, 2-propanol has no stereogenic center and is achiral. The corresponding carbon atom of 2-propanol
has an OH,H, and two methyl groups attached. Of course, no methyl carbon atom or methylene carbon can
be chiral since these groups automatically have at least two identical groups (H's) attached. The second
method, especially useful when there is more than one stereogenic center, is the use of symmetry
elements.If the molecule or object has either a plane of symmetry or a center of symmetry it is achiral.
When a molecule has two stereogenic centers, each of them can be designated as R or S. Thus there are
four possible stereoisomers. If we designate one stereocenter as "a" and the other as "b" just for labelling
purposes, the four stereoisomers can be designated as RaRb,RaSb,SaRb, and SaSb These designations
correspond to the cirucumstance that stereocenter "a" can have the R or S configuration ,and stereocenter
"b" can have either configuration. In general, if there are n such stereogenic centers , there will be a
maximum of 2n stereoisomers. For example, with three stereogenic centers, there are eight possible
stereoisomers. The maximum of 2n occurs when there are all non-equivalent stereocenters. Stereogenic
centers are equivalent when all four substituents attached to the center are identical. For example, in 2,3-
dibromobutane, both stereogenic carbons have a H, a Br, a methyl, and a 1-bromoethyl substituent. The
maximum of four stereoisomers is not observed here, as we saw before. In fact there are three
stereoisomers, including one achiral stereoisomer. This is because the 2R,3S molecule is identical to the
2S,3R molecule, since carbons 2 and 3 are equivalent. On the other hand, 2,3-dibromopentane has two non-
equivalent stereogenic centers and there are four stereoisomers, consisting of two pairs of enantiomers. It
should be noted that the relationship between one enantiomeric pair and the other pair of enantiomers is
that they are diastereoisomers..
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CHIRALITY OF ORGANIC COMPOUND
Chirality is formally defined as the geometric property of a rigid object (like a molecule or drug) of not
being superimposable with its mirror image. Molecules that can be superimposed on their mirror images
are achiral (not chiral). Chirality is a property of matter found throughout biological systems, from the
basic building blocks of life such as amino acids, carbohydrates, and lipids to the layout of the human
body. Chirality is often illustrated with the idea of left- and right-handedness: a left hand and right hand are
mirror images of each other but are not superimposable. The 2 mirror images of a chiral molecule are
termed enantiomers. Like hands, enantiomers come in pairs. Both molecules of an enantiomer pair have the
same chemical composition and can be drawn the same way in 2 dimensions (e.g., a drug structure on a
package insert), but in chiral environments such as the receptors and enzymes in the body, they can behave
differently. A racemate (often called a racemic mixture) is a mixture of equal amounts of both enantiomers
of a chiral drug. Chirality in drugs most often arises from a carbon atom attached to 4 different groups, but
there can be other sources of chirality as well. Single enantiomers are sometimes referred to as single
isomers or stereoisomers. These terms can also apply to achiral drugs and molecules and do not indicate
that a single enantiomer is present. For example, molecules that are isomers of each other share the same
stoichiometric molecular formula but may have very different structures. However, many discussions of
chiral drugs use the terms enantiomer, single isomer, and/or single stereoisomer interchangeably.
The absolute configuration at a chiral center is designated as R or S to unambiguously describe the 3-
dimensional structure of the molecule. R is from the Latin rectus and means to the right or clockwise, and S
is from the Latin sinister for to the left or counterclockwise. There are precise rules based on atomic
number and mass for determining whether a particular chiral center has an R or S configuration. A chiral
drug may have more than one chiral center, and in such cases it is necessary to assign an absolute
configuration to each chiral center. Optical rotation is often used because it is easier to determine
experimentally than absolute configuration, but it does not provide information about the absolute
configuration of an enantiomer. For a given enantiomer pair, one enantiomer can be designated (+) and the
other as (−) on the basis of the direction they rotate polarized light. Optical rotations have also been
described as dextrorotatory for (+) and levorotatory for (−). Racemates can be designated as (R,S) or (±).
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OPTICAL ACTIVITY OF CHIRAL COMPOUNDS
Since enantiomers are "handed" or "chiral", they can be distinguished by other agents which are chiral.
Thus, we can easily tell, in using our right hand to shake hands with another person, whether that person is
using his left or right hand. There is a better "fit" of the two right hands than there is of right hand to left
hand. Chemically this occurs, as noted above, when enantiomers react with another chiral compound. Both
the original enantiomer and its reactant distinguish left from right , so then one of the original enantiomers
will find a better energetic fit with the chiral compound than will the other.
One physical property which distinguishes 2 enantiomers is "optical activity". This term refers to the
property of chiral compounds (exclusively) of rotating the plane of plane-polarized light to the right
(clockwise) or to the left (counterclockwise). The two enantiomers have exactly the same ability to
rotate this plane, quantitatively, but they rotate it in opposite senses. Thus, if one enantiomer rotates
the plane by 10.5 degrees clockwise (considered a positive rotation), the other rotates it by -10.5 degrees
(i.e., in the counterclockwise direction).
Since the exact amount of the rotation of the plane by a given enantiomer depends upon how much of that
enentiomer the light encounters as it passes through the solution, the measured rotation is divided by the
concentration of the enantiomer and by the path length of the polarimeter cell to give a true measure of the
inherent ability of the enantiomer to rotate the plane of polarized light. This number is called the specific
rotation. Note that in deriving the specific rotation, the concentration is taken in grams per mL, and the
path length in decimeters. The magnitude of the rotation also depends upon the wave length of the plane
polarized light, so the a single wave length is usually used, i.e., the sodium D line (529 nm),the line
responsible for the yellow color of sodium-vapor lamps. A positive (clockwise) rotation is sometimes
called dextrorotation and a ngetaive rotation is sometimes called levorotation
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CHIRAL DRUGS AND THEIR EFFECTS AS MEDICINAL DRUG.
The majority of naturally occurring chiral molecules used for medicinal purposes are found in nature and
consequently sold as the single enantiomer. In contrast, synthesized chiral drugs are generally sold as
racemates; this is however, quickly changing. There is an increase in the desire for enantiomeric purity in
synthesized drugs because many times the distomer, the isomer that does not produce the desired biological
effect, can in fact not only be of no use but can also have bad side effects. Penicillamine has two isomers
S(-)-penicillamine, and R(+)-penicillamine, it is the S-isomer that is given to treat Wilson’s disease, a
defect in the body’s ability to metabolize copper, because it is a strong copper chelating agent. The R
isomer, in contrast, can cause blindness and is toxic. In this case the R isomer would be the distomer and
the S-isomerwould be the eutomer, because it is the isomer that produces the desired biological effect.
SelectedRacemic Drugs Currently Used in Psychiatric Practice
In the case of citalopram, the S-enantiomer is primarily responsible for antagonism of serotonin
reuptake while the R-enantiomer is 30-fold less potent.7 In clinical trials, both racemic (R,S)-
citalopram (marketed as Celexa) and (S)-citalopram (marketed as Lexapro) were significantly better
than placebo for improving depression. The early data suggest that (S)-citalopram has greater
efficacy than (R,S)-citalopram at doses predicted to be equivalent as well as equal efficacy to (R,S)-
citalopram at a dose that produces fewer side effects. Overall, (S)-citalopram appears to have
advantages over racemic citalopram and is a good example of the potential benefits of single-
enantiomer drugs. However, there is currently no evidence that patients with major depression who
are responding well to therapy with R,S-citalopram benefit from switching to S-citalopram.
In contrast, the attempt to develop a single-enantiomer formulation of fluoxetine for the treatment
of depression was unsuccessful. While (R)-fluoxetine and (S)-fluoxetine are similarly effective at
blocking serotonin reuptake, they are metabolized differently. The use of the R-enantiomer was
expected to result in less variable plasma levels of fluoxetine and its active metabolites than
observed with racemic fluoxetine. Additionally, (R)-fluoxetine and its metabolites inhibit CYP2D6,
a cytochrome P450 system enzyme, to a lesser extent than (S)-fluoxetine and its metabolites. As
mentioned, in phase II studies of (R)-fluoxetine, the highest dose led to statistically significant
prolongation of cardiac repolarization, and the studies were stopped.5 Although racemic fluoxetine
has been shown to be a safe and effective antidepressant for over 15 years, the (R)-enantiomer
formulation was not viable due to safety concerns. The experience with (S)-citalopram and (R)-
fluoxetine highlight the potential differences between enantiomers of a given chiral drug and the
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need to consider single-enantiomer formulations of a previously racemic drug on a case-by-case
Optical isomers (Thalidomide) tragedy due to Mirror Image
Enantiomers (R) and (S)
(R) effective against insomnia and morning sickness
(S) teratogenic, birth and limb defect
Mirror Image of Ibuprofen (pain killer drug) has no side effect
(S) enantiomer, effective in reducing fever and pain relief
(R) enantiomer has no side effect
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Meth Structure and its Medical uses
One chiral center, with 2 isomers R/L or S/D.
(S) isomer (Stimulant) to treat ADHD, narcolepsy, fatigue, obesity
(R) isomer is used in nasal congestion
4 stereoisomers, Ephedrine/Pseudoephedrine
All 4 optical isomers have similar properties
(1R,2S) Ephedrine and (1S,2S) Pseudoephedrine are believed to be more potent than the rest
(1S,2S) Pseudoephedrine used as a nasal decongestant and cold/flu tablet
(1R,2S) Ephedrine used for weight control - stimulate metabolic( thermogenesis ) and burning of
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The following table lists pharmaceuticals that have been available in both racemic and single-enantiomer
Racemic mixture Single-enantiomer
Amphetamine (Benzedrine) Dextroamphetamine (Dexedrine)
Bupivacaine (Marcain) Levobupivacaine (Chirocaine)
Cetirizine (Zyrtec / Reactine) Levocetirizine (Xyzal)
Citalopram (Celexa / Cipramil) Escitalopram (Lexapro / Cipralex)
Ibuprofen (Advil / Motrin) Dexibuprofen (Seractil)
Methylphenidate (Ritalin) Dexmethylphenidate (Focalin)
Milnacipran (Ixel / Savella) Levomilnacipran (Fetzima)
Modafinil (Provigil) Armodafinil (Nuvigil)
Ofloxacin (Floxin) Levofloxacin (Levaquin)
Omeprazole (Prilosec) Esomeprazole (Nexium)
Salbutamol (Ventolin) Levalbuterol (Xopenex)
Zopiclone (Imovane) Eszopiclone (Lunesta)
The following are cases where the individual enantiomers have markedly different effects:
Thalidomide: Thalidomide is racemic. One enantiomer is effective against morning sickness,
whereas the other is teratogenic. However, the enantiomers are converted into each other in vivo.
Dosing with a single-enantiomer form of the drug will still lead to both the D and L isomers
eventually being present in the patient's serum and thus would not prevent adverse effects (though it
might reduce them if the rate of in vivo conversion can be slowed).
Ethambutol: Whereas one enantiomer is used to treat tuberculosis, the other causes blindness.
Naproxen: One enantiomer is used to treat arthritis pain, but the other causes liver poisoning with
no analgesic effect.
Steroid receptor sites also show stereoisomer specificity.
Penicillin's activity is stereodependent. The antibiotic must mimic the D-alanine chains that occur in
the cell walls of bacteria in order to react with and subsequently inhibit bacterial transpeptidase
Only L-propranolol is a powerful adrenoceptor antagonist, whereas D-propranolol is not. However,
both have local anesthetic effect.
The L-isomer of Methorphan, levomethorphan is a potent opioid analgesic, while the D-isomer,
dextromethorphan is a dissociative cough suppressant.
(S)-(–) isomer of carvedilol, a drug that interacts with adrenoceptors, is 100 times more potent as
beta receptor blocker than (R)-(+) isomer. However, both the isomers are approximately equipotent
as alpha receptor blockers.
The D-isomers of amphetamine and methamphetamine are strong CNS stimulants, while the L-
isomers of both drugs lack appreciable CNS(central nervous system) stimulant effects, but instead
stimulate the peripheral nervous system. For this reason, the Levo-isomer of methamphetamine is
available as an OTC nasal inhaler in some countries, while the Dextro-isomer is banned from
medical use in all but a few countries in the world, and highly regulated in those countries who do
allow it to be used medically.
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Ketamine is commonly composed of R & S enantiomers that have different dissociative and
hallucinogenic properties, whereas the S enantiomer Esketamine is more potent in isolation as a
IMPORTANCE OF CHIRALITY IN DRUGS
Approximately 50% of marketed drugs are chiral, and of these approximately 50% are mixtures of
enantiomers rather than single enantiomers.1 In this section, the potential advantages of using single
enantiomers of chiral drugs are discussed and some specific examples of single-enantiomer drugs
currently on the market are given. Single-enantiomer drugs will become increasingly more available to the
practicing physician, and both the single-enantiomer form and the mixture of enantiomers of a given drug
may be available at the same time. In these cases, it is critical to distinguish the single enantiomer from the
racemic form because they may differ in their dosages, efficacies, side effect profiles, or even indicated
use. It is also important to realize that the safety and efficacy data for a drug evaluated as a mixture of
enantiomers are still valid. The introduction of a single-enantiomer preparation of a drug previously
approved as a mixture of enantiomers does not necessitate that the single enantiomer should become the
standard of care. The decision to use a single enantiomer versus a mixture of enantiomers of a particular
drug should be made on the basis of the data from clinical trials and clinical experience.
The increasing availability of single-enantiomer drugs promises to provide clinicians with safer, better-
tolerated, and more efficacious medications for treating patients. It is incumbent upon the practicing
physician to be familiar with the basic characteristics of chiral pharmaceuticals discussed in this article. In
particular, each enantiomer of a given chiral drug may have its own particular pharmacologic profile, and a
single-enantiomer formulation of a drug may possess different properties than the racemic formulation of
the same drug. When both a single-enantiomer and a racemic formulation of a drug are available, the
information from clinical trials and clinical experience should be used to decide which formulation is most
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