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Exploring psychotherapeutic issues and agents in clinical practice Psychopharmacology
Robert H. Howland, MD, Section Editor
2009/Digital Juice, Inc.
Clinical Implications of
Chirality and Stereochemistry
AbStRACt
Chirality, the concept of nonsuperimposable pounds containing mirror-image enantio-
mirror images, is a fundamental property of mers in equal proportions are referred to as
biological systems and can be observed on
racemic mixtures or racemates. Racemates and a molecular, cellular, or organism level. Ste- their individual enantiomers can have very reoisomer compounds possess the same mo- different pharmacological properties that lecular and structural formula, but they dif- are relevant in clinical psychopharmacology. fer in their three-dimensional configurations. Various examples of drug therapies that show Chiral compounds have two mirror-image the clinical importance of chirality and ste- stereoisomer forms called enantiomers. Com- reochemistry are described.
Robert H. Howland, MD
Journal of Psychosocial nursing • Vol. 47, no. 8, 2009 "Now, if you'l only attend, Kitty, and not talk so much, I'l tel you development of S-fluoxetine as a treatment for migraine headaches al my ideas about Looking-glass House. First, there's the room you can has had mixed results (Steiner, see through the glass—that's just the same as our drawing-room, only the Ahmed, Findley, MacGregor, & things go the other way. The books are something like our books, only Wilkinson, 1998).
the words go the wrong way…. How would you like to live in the Looking-glass House, Kitty? I wonder if they'd give you milk in there? Perhaps StIMulAnt AnD
Looking-glass milk isn't good to drink." (Carrol , 1897, pp. 20, 22) hirality, the concept of (Baumann & Eap, 2001). For ex- nonsuperimposable mir- ample, the chemical sertraline is (Focalin®) is the d-enantiomer of ror images, is a funda- a cis-(1S,4S) enantiomer that was the racemate stimulant drug meth- mental property of biological first marketed as the brand-name ylphenidate (Ritalin®). Preclini- systems and reflects the underly- product Zoloft®. Similarly, the cal studies have shown that the ing asymmetry of matter (Cintas, chemical paroxetine is a trans-(–) d-enantiomer accounts for most 2007). Indeed, chirality can be enantiomer that was first market- of the biological activity of the discerned on a molecular, cel- ed under the brand name Paxil®.
racemate methylphenidate (Heal lular, or organism level (Levin Selegiline (l-deprenyl; Eldepryl®, & Pierce, 2006). Clinical studies & Mercola, 1998). For example, Emsam®), an approved drug for suggest that dexmethylphenidate mirror-image twinning occurs in Parkinson's disease and depression, has similar or slightly greater ef- approximately 10% to 15% of is a phenylalkylamine compound ficacy than methylphenidate in monozygotic (identical) twins that structurally resembles am- (Hall, 2003). These twins exhibit phetamine. The marketed levo- disorder (ADHD), with a lower features that are mirror-image op- rotatory enantiomer (l-deprenyl) propensity for adverse effects and posite each other, such as hand- is much more biologically active can be given in half the dosage of edness, hair whorl direction, as a monoamine oxidase enzyme tooth patterns, and unilateral inhibitor compared with the dex- Amphetamine products are eye and ear defects. Stereoisomer trorotatory enantiomer (Yasar et available as dextroamphetamine compounds possess the same mo- lecular and structural formula but Citalopram (Celexa®) is a dextroamphetamine have different three-dimensional racemic mixture. The phar- lisdexamfetamine configurations. Chiral com- macological activity of citalo- (Vyvanse®). Dextroamphetamine pounds have two mirror-image pram (serotonin reuptake in- is the d-enantiomer of the race- stereoisomers called enantiomers. hibition) is mostly attributable mate drug amphetamine (Patrick Compounds containing mirror- to the S-enantiomer, and the & Markowitz, 1997). Dextroam- image enantiomers in equal pro- R-enantiomer may competitively phetamine and levoamphetamine portions are referred to as racemic interfere with this effect (Sán- have differential effects on the mixtures or racemates. Last month, chez, Bøgesø, Ebert, Reines, & neurotransmitters dopamine and I described the main principles Braestrup, 2004). For this reason, norepinephrine and on the meta- of chirality and stereochemistry, the S-enantiomer escitalopram bolic enzyme monoamine oxidase, which are essential for under- (Lexapro®) was further devel- and their pharmacokinetic pro- standing the three-dimensional oped as an antidepressant drug.
files are somewhat different. Early aspects of psychopharmacology. Fluoxetine (Prozac®) is a studies suggested that both drugs In this article, I will review ex- racemate. The R-fluoxetine and were effective overall for treating amples of drug therapies in which S-fluoxetine enantiomers have ADHD, but they appeared to have chirality and stereochemistry are differential effects on neurotrans- differential effects on attention mitter transporters, liver metabol- and hyperactivity. Levoamphet- ic enzymes, and cardiac function. amine is not marketed separately The development of R-fluoxetine but is present in small amounts in Most antidepressant drugs ex- as a more "pure" antidepressant ist as racemic mixtures and are molecule was halted because of amine combination products.
marketed in this form, but several increased adverse cardiac effects Prodrugs are pharmacological- are sold as specific enantiomers (Shah, 2002), whereas further ly inactive compounds that are converted to biologically active otHeR DRugS
in Parkinson's disease found that metabolites. Lisdexamfetamine is Thalidomide (Thalomid®) was the most significant side effects of an inactive prodrug in which the originally developed and mar- the drug were attributable to the enantiomer dextroamphetamine keted in the 1950s as a sedative D-dopa enantiomer (Coutts & is chemically bonded to the medication for treating morning Baker, 1989).
amino acid enantiomer L-lysine sickness during pregnancy. It was Esomeprazole (Nexium®), a (Howland, 2008). After oral in- subsequently withdrawn when proton pump inhibitor used to gestion, the bond is metabolically found to be associated with sig- suppress gastric acid secretion, cleaved in the gut, and lisdexam- nificant birth defects but was lat- is the S-enantiomer of the race- fetamine is converted to L-lysine er reintroduced for treating other mate omeprazole (Prilosec®). The and to the pharmacologically ac- medical conditions. Thalidomide drugs have different pharmacoki- tive drug dextroamphetamine. exists as a racemic mixture of R- netic properties: Esomeprazole Compared with regular orally and S- enantiomers. Studies have has less first-pass hepatic metabo- dextroamphetamine, shown that the S-thalidomide lism, a lower plasma clearance, exposure to dextroamphetamine that is released from lisdexamfe-tamine is decreased and delayed Most antidepressant drugs exist as racemic mixtures and are in an extended-release pattern.
Pseudoephedrine (Sudafed®), marketed in this form, but several are sold as specific approved for nasal sinus conges- tion, is the dextro-enantiomer form of the racemate ephedrine (Mistole®), which is approved for nasal congestion and acute enantiomer may have been se- and greater oral bio- bronchospasm. It is approximate- lectively responsible for the birth availability compared ly one fourth as potent as ephed- defects associated with use of with omeprazole (Dent, 2003).
rine as a sympathomimetic agent, thalidomide (Waldeck, 2003).
Pregabalin (Lyrica®) is a with much fewer adverse cardio- The thyroid hormone thyrox- chemical analog of the inhibitory vascular effects (Drew, Knight, ine exists as a racemic mixture of amino acid gamma-aminobutyric Hughes, & Bush, 1978).
levothyroxine (L-thyroxine) and acid (GABA). It is approved for Modafinil (Provigil®) is a ra- dextrothyroxine (D-thyroxine). the treatment of diabetic neu- cemic stimulant-like drug (un- Levothyroxine (Levoxyl®, Syn- ropathy and fibromyalgia. Pre- related to methylphenidate or throid®) is used as replacement gabalin is the pharmacologically amphetamine). It is approved therapy for hypothyroidism. active S-enantiomer of racemic for the treatment of excessive 3-isobutyl GABA (Frampton & daytime sleepiness associated is much less potent than levo- Foster, 2006). Compared with the with narcolepsy, sleep apnea, thyroxine. It is approved for the racemate, pregabalin binds with and shift work sleep disorder. treatment of hypercholesterol- higher affinity to a particular site The R-modafinil enantiomer has emia but is no longer commer- of the GABA receptor complex a half-life that is significantly cially available. The drug was in the central nervous system.
longer than that of S-modafinil, associated with a significantly and the elimination of S- higher rate of cardiovascular is a marketed hypnotic agent modafinil is about three times mortality in clinical trials, and (Lunesta®) for insomnia. It is the faster than R-modafinil (Wisor, the manufacturer ceased produc- S-enantiomer of racemic zopi- Dement, Aimone, Williams, & tion (Denke, 2005).
clone (Imovane®), which is not Bozyczko-Coyne, 2006). Because Dopa is an amino acid pre- available in the United States R-modafinil is expected to have cursor of the neurotransmitter but is marketed elsewhere for the a longer daytime therapeutic ef- dopamine, and it exists as a race- treatment of insomnia. Preclini- fect than racemic modafinil, the mic mixture of the enantiomers cal trials demonstrated that the R-modafinil enantiomer (Nu- levodopa (L-dopa) and dextro- S-enantiomer was more active vigil®) has been approved for dopa (D-dopa). Levodopa is used at the benzodiazepine receptor the same indications as racemic for the treatment of Parkinson's complex than the R-enantiomer disease. The early studies of dopa and contributed to most of the Journal of Psychosocial nursing • Vol. 47, no. 8, 2009 hypnotic activity of racemic zopi- has little or no analgesic activ- clone (Lane & Baker, 1999).
ity (Burke & Kratochvil, 2002). Baumann, P., & Eap, C.B. (2001). Enan- tiomeric antidepressant drugs should Ketamine (Ketolar®), an an- Although no longer manufac- be considered on individual merit. esthetic agent derived from the tured, the levopropoxyphene Human Psychopharmacology: Clinical hallucinogenic drug phencycli- enantiomer was once marketed and Experimental, 16(Suppl. 2), S85- dine (PCP), is a racemate that as a centrally acting cough sup- has been investigated for treat- pressant with the trade name Burke, D., & Henderson, D.J. (2002). Chirality: A blueprint for the future. ment-resistant depression. Com- Novrad® (Darvon spelled back- British Journal of Anaesthesia, 88, 563- pared with racemate ketamine, the S-ketamine enantiomer is Burke, W.J., & Kratochvil, C.J. (2002). less likely to cause perceptual Stereoisomers in psychiatry: The case disturbances and confusion, Alice wondered whether of escitalopram. Primary Care Com-panion to the Journal of Clinical Psy- while preserving its anesthetic Looking-glass milk might not chiatry, 4, 20-24.
Carroll, L. (1897). Through the looking- glass, and what Alice found there. Phila-delphia: Henry Altemus.
Profound differences can sometimes be Cintas, P. (2007). Tracing the origins and evolution of chirality and handedness demonstrated between different chemical in chemical language. Angewandte Chemie International Edition, 46, enantiomers. Coutts, R.T., & Baker, G.B. (1989). Im- plications of chirality and geometric isomerism in some psychoactive drugs and their metabolites. Chirality, 1, and potential antidepressant ef- be good to drink. If one consid- fects (Burke & Henderson, 2002; ers the chemical constituents Denke, M.A. (2005). Diet, lifestyle, and Paul, Schaaff, Padberg, Moller, & of milk, it would certainly be nonstatin trials: Review of time to Frodl, 2007).
reasonable to speculate about benefit. American Journal of Cardiol-ogy, 96(5A), 3F-10F.
Methadone (Dolophine®), a the possible physiological dif- Dent, J. (2003). Review article: Phar- synthetic opioid analgesic, is a ferences in mirror-image milk. macology of esomeprazole and com- racemate. The R-methadone en- Odors and tastes are chemically parisons with omeprazole. Alimen- antiomer is more pharmacologi- mediated, and profound differ- tary Pharmacology and Therapeutics, cally active and potent than ences can sometimes be demon- 17(Suppl. 1), 5-9.
Drew, C.D., Knight, G.T., Hughes, D.T., S-methadone. The metabolism strated between different chemi- & Bush, M. (1978). Comparison of of racemate methadone in the cal enantiomers (Sell, 2004; the effects of D-(-)-ephedrine and liver is stereospecific, which Temussi, 2009). For example, L-(+)-pseudoephedrine on the car- means that each enantiomer is the dipeptide combination of diovascular and respiratory systems in metabolized differently by vari- the amino acids L-aspartic acid man. British Journal of Clinical Pharma-cology, 6, 221-225.
ous hepatic enzymes. Taking and L-phenyl-alanine methyl Frampton, J.E., & Foster, R.H. (2006). medications that selectively in- ester (L-Asp-L-PheOMe) is Pregabalin: In the treatment of gen- hibit the metabolic enzyme that manufactured as the artificial eralized anxiety disorder. CNS Drugs, stereospecifically sweetener aspartame. However, 20, 685-693.
the R-methadone enantiomer this dipeptide combination can Hall, J.G. (2003). Twinning. Lancet, 362, may increase R-methadone con- exist in four stereoisomer forms. Heal, D.J., & Pierce, D.M. (2006). Meth- centrations, potentially resulting The stereoisomers D-Asp-D- ylphenidate and its isomers: Their in greater analgesic and adverse PheOMe, D-Asp-L-PheOMe, role in the treatment of attention- effects (Uehlinger et al., 2007).
and L-Asp-D-PheOMe are bit- deficit hyperactivity disorder using Propoxyphene, an opioid ter. Because the introduction a transdermal delivery system. CNS Drugs, 20, 713-738.
analgesic structurally related of stereochemically pure drugs Howland, R.H. (2008). Lisdexamfetamine: to methadone, exists as a race- is expected to increase, nurses A prodrug stimulant for ADHD. Jour- mate. The dextropropoxyphene should understand the rationale nal of Psychosocial Nursing and Mental enantiomer is marketed as an for their development and how Health Services, 46(8), 19-22.
analgesic (Darvon®) because the they may improve the pharma- Lane, R.M., & Baker, G.B. (1999). Chi- rality and drugs used in psychiatry: levopropoxyphene enantiomer cotherapy of patient care.
Nice to know or need to know? Cel- Shah, R.R. (2002). The significance of effects and pharmacokinetic profile lular and Molecular Neurobiology, 19, QT interval in drug development. in the rat. Pharmacology, Biochemis- British Journal of Clinical Pharmacol- try, and Behavior, 85, 492-499.
Levin, M., & Mercola, M. (1998). The ogy, 54, 188-202.
Yasar, S., Gaál, J., Panlilio, L.V., Justi- compulsion of chirality: Toward an Steiner, T.J., Ahmed, F., Findley, L.J., nova, Z., Molnár, S.V., Redhi, G.H., understanding of left-right asymme- MacGregor, E.A., & Wilkinson, M. et al. (2006). A comparison of drug- try. Genes and Development, 12, 763- (1998). S-fluoxetine in the prophy- seeking behavior maintained by laxis of migraine: A phase II double- D-amphetamine, L-deprenyl (selegi- Patrick, K.S., & Markowitz, J.S. (1997). blind randomized placebo-controlled line), and D-deprenyl under a second- Pharmacology of methylphenidate, study. Cephalalgia, 18, 283-286.
order schedule in squirrel monkeys. Temussi, P.A. (2009). Sweet, bitter and Psychopharmacology, 183, 413-421.
pemoline in attention-deficit hyper- umami receptors: A complex rela- activity disorder. Human Psychophar- tionship. Trends in Biochemical Sci- macology: Clinical and Experimental, ences, 34, 296-302.
Dr. Howland is Associate Professor 12, 527-546.
Uehlinger, C., Crettol, S., Chassot, P., of Psychiatry, University of Pittsburgh Paul, R., Schaaff, N., Padberg, F., Moller, Brocard, M., Koeb, L., Brawand- School of Medicine, Western Psychiatric H.J., & Frodl, T. (2007). Comparison Amey, M., et al. (2007). Increased Institute and Clinic, Pittsburgh, Pennsyl- of racemic ketamine and S-ketamine (R)-methadone plasma concentra- in treatment-resistant depression: Re- tions by quetiapine in cytrochrome The author discloses that he has port of two cases. World Journal of Bio- P450s and ABCB1 genotyped pa- no significant financial interests in any logical Psychiatry. First published online tients. Journal of Clinical Psychophar- product or class of products discussed October 29, 2007. doi: 10.1080/15622 macology, 27, 273-278.
directly or indirectly in this activity, Waldeck, B. (2003). Three-dimensional including research support. Sánchez, C., Bøgesø, K.P., Ebert, B., pharmacology, a subject ranging Address correspondence to Robert Reines, E.H., & Braestrup, C. (2004). from ignorance to overstatements. H. Howland, MD, Associate Professor Escitalopram versus citalopram: The Pharmacology and Toxicology, 93, of Psychiatry, University of Pittsburgh surprising role of the R-enantiomer. School of Medicine, Western Psychiatric Psychopharmacology, 174, 163-176.
Wisor, J.P., Dement, W.C., Aimone, L., Institute and Clinic, 3811 O'Hara Sell, C.S. (2004). Scent through the look- Williams, M., & Bozyczko-Coyne, D. Street, Pittsburgh, PA 15213; e-mail: ing glass. Chemistry and Biodiversity, 1, (2006). Armodafinil, the R-enantio- mer of modafinil: Wake-promoting

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