Stereochemistry in Drug Action
`
`Stereochemistry in Drug Action
`
`Jonathan McConathy, Ph.D., and Michael J. Owens, Ph.D.
`
`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. Many of the drugs currently used in psy-
`chiatric practice are mixtures of enantiomers.
`For some therapeutics, single-enantiomer formu-
`lations can provide greater selectivities for their
`biological targets, improved therapeutic indices,
`and/or better pharmacokinetics than a mixture of
`enantiomers. This article reviews the nomencla-
`ture for describing stereochemistry and enanti-
`omers, emphasizes the potential biological and
`pharmacologic differences between the 2 enanti-
`omers of a drug, and highlights the clinical expe-
`rience with single enantiomers of the selective
`serotonin reuptake inhibitors fluoxetine and
`citalopram. In some cases, both a mixture of en-
`antiomers 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 prac-
`ticing physician to provide optimal pharma-
`cotherapy to his or her patients.
`(Primary Care Companion J Clin Psychiatry 2003;5:70–73)
`
`Received March 3, 2003; accepted April 25, 2003. From the
`Laboratory of Neuropsychopharmacology, Department of Psychiatry &
`Behavioral Sciences, Emory University School of Medicine, Atlanta, Ga.
`Supported by an unrestricted grant from Forest Laboratories
`(Dr. Owens).
`Dr. Owens has received grant/research support from Forest, Cypress
`Bioscience, GlaxoSmithKline, and Pfizer.
`Corresponding author and reprints: Michael J. Owens, Ph.D.,
`Laboratory of Neuropsychopharmacology, Department of Psychiatry &
`Behavioral Sciences, 1639 Pierce Dr., Ste. 4000, Emory University School
`of Medicine, Atlanta, GA 30322 (e-mail: mowens@emory.edu).
`
`CHIRALITY AND ENANTIOMERS
`
`This section contains the basics needed to understand
`chiral drugs. Undergraduate textbooks in chemistry are
`good resources for a more thorough discussion of chiral-
`ity and enantiomers. The most important point is that chi-
`ral drugs have 2 structurally similar forms that can behave
`very differently in biological systems due to their differ-
`ent shapes in 3-dimensional space. These 2 possible forms
`are termed enantiomers, and the 2 enantiomers of a given
`chiral drug should be considered 2 different drugs. This
`topic is discussed further in the next section.
`
`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 lay-
`out 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 super-
`imposable. 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 in-
`sert), 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 some-
`times 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 ex-
`ample, 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 2 enantiomers of a chiral drug are best identified
`on the basis of their absolute configuration or their optical
`rotation. Other designations such as D and L (note the up-
`per case) are used for sugars and amino acids but are spe-
`cific to these molecules and are not generally applicable
`to other compounds. The terms d, or dextro, and l, or levo,
`are considered obsolete and should be avoided. Instead,
`the R/S system for absolute configuration and the +/– sys-
`tem for optical rotation should be used. The absolute con-
`figuration at a chiral center is designated as R or S to un-
`ambiguously 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 par-
`ticular 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
`
`© COPYRIGHT 2003 PHYSICIANS POSTGRADUATE PRESS, INC. © COPYRIGHT 2003 PHYSICIANS POSTGRADUATE PRESS, INC.
`Primary Care Companion J Clin Psychiatry 2003;5(2)
`
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`Coalition for Affordable Drugs IV LLC – Exhibit 1008
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`

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`McConathy and Owens
`
`Figure 1. The Hypothetical Interaction Between the 2 Enantiomers of a Chiral Drug and Its Binding Sitea
`
`Mirror Plane
`
`Active Enantiomer
`D
`
`Inactive Enantiomer
`D
`
`Inactive Enantiomer
`A
`
`Rotation
`
`B
`
`A
`
`C
`
`b
`
`C
`
`×
`
`B
`
`b
`
`A
`
`×
`
`B
`
`C
`
`D
`
`×
`
`b
`
`a
`
`c
`
`a
`
`c
`
`a
`
`A
`
`c
`
`Drug Binding Site
`
`Drug Binding Site
`
`Drug Binding Site
`
`aThe active enantiomer has a 3-dimensional structure that allows drug domain A to interact with binding site domain a,
`B to interact with b, and C to interact with c. In contrast, the inactive enantiomer cannot be aligned to bind the same
`3 sites simultaneously. The difference in 3-dimensional structure allows the active enantiomer to bind and have a
`biological effect, whereas the inactive enantiomer cannot.
`
`each chiral center. Optical rotation is often used because
`it is easier to determine experimentally than absolute con-
`figuration, but it does not provide information about the
`absolute configuration of an enantiomer. For a given en-
`antiomer pair, one enantiomer can be designated (+) and
`the other as (–) on the basis of the direction they rotate po-
`larized light. Optical rotations have also been described as
`dextrorotatory for (+) and levorotatory for (–). Racemates
`can be designated as (R,S) or (±).
`
`CHIRAL DRUGS IN BIOLOGICAL SYSTEMS
`
`Enantiomers of a chiral drug have identical physical
`and chemical properties in an achiral environment. In a
`chiral environment, one enantiomer may display different
`chemical and pharmacologic behavior than the other en-
`antiomer. Because living systems are themselves chiral,
`each of the enantiomers of a chiral drug can behave very
`differently in vivo. In other words, the R-enantiomer of a
`drug will not necessarily behave the same way as the
`S-enantiomer of the same drug when taken by a patient.
`For a given chiral drug, it is appropriate to consider the 2
`enantiomers as 2 separate drugs with different properties
`unless proven otherwise.
`The difference between 2 enantiomers of a drug is
`illustrated in Figure 1 using a hypothetical interaction be-
`tween a chiral drug and its chiral binding site. In this case,
`one enantiomer is biologically active while the other en-
`antiomer is not. The portions of the drug labeled A, B, and
`C must interact with the corresponding regions of the
`binding site labeled a, b, and c for the drug to have its
`pharmacologic effect. The active enantiomer of the drug
`has a 3-dimensional structure that can be aligned with the
`binding site to allow A to interact with a, B to interact with
`
`b, and C to interact with c. In contrast, the inactive enanti-
`omer cannot bind in the same way no matter how it is
`rotated in space. Although the inactive enantiomer pos-
`sesses all of the same groups A, B, C, and D as the active
`enantiomer, they cannot all be simultaneously aligned
`with the corresponding regions of the binding site.
`This difference in 3-dimensional structure prevents the
`inactive enantiomer from having a biological effect at this
`binding site. In some cases, the portion of a molecule con-
`taining the chiral center(s) may be in a region that does
`not play a role in the molecule’s ability to interact with its
`target. In these instances, the individual enantiomers may
`display very similar or even equivalent pharmacology at
`their target site. Even in these cases, the enantiomers may
`differ in their metabolic profiles as well as their affinities
`for other receptors, transporters, or enzymes.
`
`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 poten-
`tial 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 effi-
`cacy data for a drug evaluated as a mixture of enantiomers
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`© COPYRIGHT 2003 PHYSICIANS POSTGRADUATE PRESS, INC. © COPYRIGHT 2003 PHYSICIANS POSTGRADUATE PRESS, INC.
`Primary Care Companion J Clin Psychiatry 2003;5(2)
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`Table 1. Selected Racemic Drugs Currently Used
`in Psychiatric Practice
`Bupropiona
`Citalopramb
`Fluoxetine
`Methylphenidateb
`Thioridazine (and some other phenothiazines)
`Tranylcypromine
`Trimipramine
`Venlafaxine
`Zopiclonea
`aSingle-enantiomer formulation under development.
`bSingle-enantiomer form also available.
`
`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 enanti-
`omer 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 2 enantiomers of a chiral drug may differ sig-
`nificantly in their bioavailability, rate of metabolism,
`metabolites, excretion, potency and selectivity for re-
`ceptors, transporters and/or enzymes, and toxicity. The
`use of single-enantiomer drugs can potentially lead to
`simpler and more selective pharmacologic profiles, im-
`proved therapeutic indices, simpler pharmacokinetics due
`to different rates of metabolism of the different enanti-
`omers, and decreased drug interactions. For example, one
`enantiomer may be responsible for the therapeutic effects
`of a drug whereas the other enantiomer is inactive and/or
`contributes to undesirable effects. In such a case, use of
`the single enantiomer would provide a superior medica-
`tion and may be preferred over the racemic form of the
`drug. Single-enantiomer formulations of (S)-albuterol, a
`β2-adrenergic receptor agonist for treatment of asthma,
`and (S)-omeprazole, a proton pump inhibitor for treat-
`ment of gastroesophageal reflux, have been shown to be
`superior to their racemic formulations in clinical trials.2 In
`other cases, however, both enantiomers of a chiral drug
`may contribute to the therapeutic effects, and the use of a
`single enantiomer may be less effective or even less safe
`than the racemic form. For example, the (–)-enantiomer
`of sotalol has both β-blocker and antiarrhythmic activity,
`whereas the (+)-enantiomer has antiarrhythmic properties
`but lacks β-adrenergic antagonism.3,4 In addition, the R-
`enantiomer of fluoxetine, at its highest administered dose,
`led to statistically significant prolongation of cardiac re-
`polarization in phase II studies; the studies were subse-
`quently stopped.5
`Currently, there is no regulatory mandate in the United
`States or Europe to develop new drugs exclusively as
`single enantiomers. The U.S. Food and Drug Admin-
`istration (FDA) policy regarding single enantiomers was
`published in 1992. This statement is available at the FDA
`
`Stereochemistry in Drug Action
`
`Web site at www.fda.gov/cder/guidance/stereo.htm. The
`FDA leaves the decision to pursue a racemic or a single-
`enantiomer formulation of a new drug to its developers,
`but the choice of a racemic versus a single-enantiomer for-
`mulation must be justified. Although both racemic and
`single-enantiomer drugs will continue to be developed, a
`higher proportion of single enantiomers are being submit-
`ted for new drug approval.6
`Although many psychotropic drugs are either achiral
`(e.g., fluvoxamine, nefazodone) or are already marketed
`as single enantiomers (e.g., sertraline, paroxetine, escita-
`lopram), a number of antidepressants are currently mar-
`keted as racemates, including bupropion, citalopram, flu-
`oxetine, tranylcypromine, trimipramine, and venlafaxine.
`Other drugs often used in psychiatric practice including
`zopiclone, methylphenidate, and some phenothiazines are
`also available as racemates. Of these, single-enantiomer
`formulations are being developed for bupropion and zop-
`iclone. Dexmethylphenidate (d-methylphenidate) has also
`been introduced recently. Selected racemic drugs used in
`psychiatric practice are listed in Table 1. An instructive
`comparison can be made between the development of the
`single-enantiomer formulations of citalopram and fluoxe-
`tine. In both cases, one enantiomer appeared to have supe-
`rior in vivo properties, and clinical trials were conducted
`to determine the safety and efficacy of (S)-citalopram and
`(R)-fluoxetine.
`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.8–11 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.12,13 Overall, (S)-citalopram appears to
`have advantages over racemic citalopram and is a good ex-
`ample 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.5 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.14 As mentioned, in phase II studies of (R)-
`fluoxetine, the highest dose led to statistically significant
`prolongation of cardiac repolarization, and the studies were
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`© COPYRIGHT 2003 PHYSICIANS POSTGRADUATE PRESS, INC. © COPYRIGHT 2003 PHYSICIANS POSTGRADUATE PRESS, INC.
`Primary Care Companion J Clin Psychiatry 2003;5(2)
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`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 need to consider
`single-enantiomer formulations of a previously racemic
`drug on a case-by-case basis.
`
`SUMMARY
`
`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 phar-
`macologic profile, and a single-enantiomer formulation
`of a drug may possess different properties than the race-
`mic 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 appropriate.
`
`Drug names: albuterol (Ventolin, Proventil, and others), bupropion
`(Wellbutrin and others), citalopram (Celexa), dexmethylphenidate
`(Focalin), escitalopram (Lexapro), fluoxetine (Prozac and others),
`fluvoxamine (Luvox and others), methylphenidate (Ritalin, Concerta,
`and others), nefazodone (Serzone), omeprazole (Prilosec and others),
`paroxetine (Paxil), sertraline (Zoloft), tranylcypromine (Parnate),
`trimipramine (Surmontil), venlafaxine (Effexor).
`
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`© COPYRIGHT 2003 PHYSICIANS POSTGRADUATE PRESS, INC. © COPYRIGHT 2003 PHYSICIANS POSTGRADUATE PRESS, INC.
`Primary Care Companion J Clin Psychiatry 2003;5(2)
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