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The importance of stereochemistry in drug action

Fuse809 October 2, 2014 User blog:Fuse809

Did you know that most newer antidepressants (e.g., sertraline, mirtazapine) and drugs for attention-deficit/hyperactivity disorder (ADHD) and sleep disorders (e.g., atomoxetine, dexamfetamine, lisdexamfetamine, methylphenidate, modafinil, etc.) exhibit chirality? The same is true of ketamine, a veterinary tranquillizer turned miracle drug for treatment-resistant cases of depression.

Background

Main page: Chirality

Chirality for those of you that do not belong to a field that requires first year university chemistry knowledge, is basically a fancy way of saying mirror image forms of the same drug molecule. They are created using They are assigned either (R) or (S) designations based on the CIP rules which we use to distinguish the two mirror image forms based on their orientation. We call these two mirror forms, stereoisomers. (R)-enantiomers are orientated to the right according to the CIP rules and (S)-enantiomers are orientated towards the left.

Impact of chirality on pharmacology: the thalidomide disaster

The two stereoisomers of a drug molecule often have vastly different biological activities. For example, thalidomide is an example that my chemistry professor from last year loved to mention. Ironically this professor is German and thalidomide was initially synthesized and marketed by a German pharmaceutical company. Thalidomide has two enantiomers: the (S)-enantiomer believed to be responsible for the birth defects caused by thalidomide whilst the (R)-enantiomer produces its therapeutic effects. Funnily enough it did not matter whether or not the (R)-enantiomer was served by itself or not as in the body it is quickly converted to the (S)-enantiomer too, hence negating any value from separating the two.

Examples

Note: further information on the drugs mentioned may be found on the drug's monograph in this Wiki. Psychiatric drugs that have stereochemistry include (but are not limited to):

Antidepressants

All MAOIs except pirlindole, selegiline and tranylcypromine have no stereocentres. All TCAs except trimipramine are without stereocentres.

Structure
Bupropion
Bupropion's 2D structure
  • Bupropion, comes as a racemate of the two enantiomers. A single enantiomer of bupropion was apparently under investigation in 2003, although this is according to just one source I have come across.[1]


Structure
Citalopram racemate
2D structure of the racemate of citalopram
  • Citalopram, it is sold as a racemate, which contains both enantiomers in equal quantities. (S)-citalopram is the active enantiomer whereas the (R)-enantiomer may even negate some of the therapeutic effects of the (S)-enantiomer. The racemic mixture of both (R)- and (S)-citalopram is also more likely to adversely affect the heart than the pure (S)-enantiomer.[1] It is a selective serotonin reuptake inhibitor.


Structure
Escitalopram
Escitalopram's 2D structure
  • Escitalopram, the pure (S)-enantiomer of citalopram. It is superior to citalopram and most other antidepressants in how effective it is at relieving depression, although the differences between the effectiveness of antidepressants are generally so minor that it does not really make any difference on the scale of a patient and their prescribing physician.[2] This is because the difference is so minor that, on average, one would have to treat over twenty people with both drugs (>twenty people assigned to each) in order for one to see one more patient benefit from one than the other (e.g., odds are, out of a total of say 80 patients, randomly allocated to receive either one drug or the other less effective drug you would expect say 28 patients to respond to the less effective agent and 29 patients to respond to the more effective agent). It is a selective serotonin reuptake inhibitor.


Racemic structure
Desvenlafaxine racemate
Structure of desvenlafaxine as a racemate


Structure
Duloxetine
Duloxetine's 2D structure


Structure
Fluoxetine racemate
Racemic fluoxetine's 2D structure
  • Fluoxetine, both enantiomers are equally effective at increasing brain serotonin levels and hence also at relieving depression, but the (R)-enantiomer has more predictable pharmacokinetics. Pure (R)-fluoxetine was being developed as a treatment for depression until it was discovered that its effects on the heart were too significant for it to be of use, medically.[1] It is a selective serotonin reuptake inhibitor.


Structure
Milnacipran
Milnacipran's 2D structure


Structure
Mianserin racemate
2D structure of racemic mianserin


Structure
Mirtazapine racemate
2D structure of racemic mirtazapine
  • Mirtazapine, also comes as a racemic mixture of the two enantiomers. The S(+)-enantiomer is responsible for the drug's actions at the 5-HT2 receptors, whereas the R(—)-enantiomer is responsible for its actions at the 5-HT3 receptors. It too is a NaSSA.


Structure
Paroxetine
Paroxetine's 2D structure
  • Paroxetine, only one stereoisomer is available for medical use. Specifically the (3S,4R)-stereoisomer. It too is a SSRI.


Structure
Reboxetine racemate
Reboxetine's 2D structure


Structure
Sertraline
Sertraline's 2D structure


Structure
Tranylcypromine racemate
Tranylcypromine's 2D structure
  • Tranylcypromine, both the (1R,2S)(—) and (1S,2R)(+)-stereoisomers are present in the racemate. The (+)-enantiomer inhibits monoamine oxidase, whereas the (—)-enantiomer acts in a similar way to the amfetamines, to which it is chemically related. It is an irreversible monoamine oxidase inhibitor.[3]


Structure
Trimipramine racemate
Trimipramine's 2D structure


Structure
Venlafaxine racemate
Racemic venlafaxine's 2D structure
  • Venlafaxine, comes as a racemic mixture, with no major difference between the two in as far as their biological effect is known. It inhibits the reuptake of serotonin and noradrenaline, with a significant preference for the former neurotransmitter.



ADHD and narcolepsy medicines

Structure
Amfetamine
Amfetamine's 2D structure
  • Amfetamine, usually in the form of mixed amfetamine salts, is used in the management of ADHD in North America and a small handful of European countries. It comes as a mixture of the R(—)- and S(+)-enantiomers, approximately three-quarters are made up of the S(+)-enantiomer and the remaining quarter is made up of R(—)-amfetamine. The S(+)-enantiomer is significantly more active at inducing the release and inhibiting the reuptake of dopamine than the R(—)-enantiomer, although the R(—)-enantiomer produces more prominent peripheral effects like increased blood pressure and heart rate, constipation, dry mouth, etc.


Structure
Atomoxetine
Atomoxetine's 2D structure
  • Atomoxetine comes solely as the (R)-enantiomer. It is a significantly selective noradrenaline reuptake inhibitor, although a weak, yet clinically significant (most as far as the potential for it to contribute to serotonin syndrome) effect on serotonin reuptake is usually seen at clinically-utilized doses. It is a first-line treatment for the condition, along with methylphenidate.


Structure
Dexamfetamine
Dexamfetamine's 2D structure
  • Dexamfetamine is the (S) enantiomer of amfetamine. It is a second-line treatment for ADHD in most of the developed world, including Australia, Canada, New Zealand, the UK and the U.S.A. It is also used in the management of narcolepsy.


Structure
Dexmethylphenidate
Dexmethylphenidate's 2D structure
  • Dexmethylphenidate is the pure and more active S(+)-enantiomer of methylphenidate. Used solely in the management of ADHD and only available in select countries such as the U.S.A.


Structure
Metamfetamine
Metamfetamine's 2D structure
  • Metamfetamine is only marketed in the U.S.A., where it as the pure S(+)-enantiomer, for the treatment of resistant cases of ADHD and obesity. Although the R(—)-enantiomer is also available for use in the management of nasal congestion (i.e., a runny nose) in the U.S.A.


Structure
Methylphenidate
Methylphenidate's 2D structure
  • Methylphenidate is only stimulant medicine that is approved for the first-line treatment of ADHD; it is also used in the treatment of narcolepsy. It is available in virtually every developed country worldwide and is usually rather inexpensive. It is unlike the amfetamines in that it is solely a noradrenaline-dopamine reuptake inhibitor, with no appreciable ability to directly induce the release of these two neurotransmitters.


Structure
Modafinil
Modafinil's 2D structure
  • Modafinil is used in the management of narcolepsy, primarily, although it can be used, usually as a third or fourth-line treatment, for the management of ADHD. The (R)-enantiomer is the more active form and is also marketed under the generic name of armodafinil. It is not technically a stimulant, as it does not usually produce euphoria, neither does it possess any significant abuse liability. Its exact mechanism of action is unknown but it is known to be a weak dopamine reuptake inhibitor.

Reference list

  1. 1.0 1.1 1.2 McConathy, J; Owens, MJ (April 2003). "Stereochemistry in Drug Action.". Primary Care Companion to the Journal of Clinical Psychiatry 5 (2): 70–73. PMC 353039. PMID 15156233. 
  2. Cipriani, A; Furukawa, TA; Salanti, G; Geddes, JR; Higgins, JP; Churchill, R; Watanabe, N; Nakagawa, A; Omori, IM; McGuire, H; Tansella, M; Barbui, C (February 2009). "Comparative efficacy and acceptability of 12 new-generation antidepressants: a multiple-treatments meta-analysis." (PDF). Lancet 373 (9665): 746–58. PMID 19185342. doi:10.1016/S0140-6736(09)60046-5. 
  3. Frieling, H; Bleich, S (August 2006). "Tranylcypromine: new perspectives on an "old" drug.". European Archives of Psychiatry and Clinical Neuroscience 256 (5): 268–73. PMID 16927039. doi:10.1007/s00406-006-0660-8. 

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