The eudysmic ratio (also spelled eudismic ratio) represents the difference in
pharmacologic activity between the two
enantiomers
In chemistry, an enantiomer ( /ɪˈnænti.əmər, ɛ-, -oʊ-/ ''ih-NAN-tee-ə-mər''; from Ancient Greek ἐνάντιος ''(enántios)'' 'opposite', and μέρος ''(méros)'' 'part') – also called optical isomer, antipode, or optical anti ...
of a drug. In most cases where a
chiral compound is biologically active, one enantiomer is more active than the other. The eudysmic ratio is the ratio of activity between the two. A eudysmic ratio
significantly differing from 1 means that they are statistically different in activity. Eudisimic ratio (ER) reflects the degree of enantioselectivity of the biological systems. For example, (S)-propranolol (ER = 130) meaning that (S)-propranolol is 130 times more active as its (R)-enantiomer.
Terminology
The eutomer is the enantiomer having the desired pharmacological activity, e.g., as an active ingredient in a drug.
The distomer, on the other hand, is the enantiomer of the eutomer which may have undesired bioactivity or may be bio-inert.
A
racemic mixture
In chemistry, a racemic mixture, or racemate (), is one that has equal amounts of left- and right-handed enantiomers of a chiral molecule or salt. Racemic mixtures are rare in nature, but many compounds are produced industrially as racemates. ...
is an equal mixture of both enantiomers, which may be easier to manufacture than a single enantiomeric form.
![Indacrinone Enantiomers](https://upload.wikimedia.org/wikipedia/commons/6/65/Indacrinone_Enantiomers.png)
It is often the case that only a single one of the enantiomers contains all of the wanted bioactivity, the distomer is often less active, has no desired activity or may even be toxic.
In some cases, the eudysmic ratio is so high, that it is desired to separate out the two enantiomers instead of leaving it as a racemic product. It is also possible that the distomer is not simply completely inactive but actually
antagonizes the effects of the eutomer. There are a few examples of chiral drugs where both the enantiomers contribute, in different ways, to the overall desired effect. An interesting situation is that in which the distomer antagonizes a side-effect of the eutomer for the desired action, mutually beneficial action form therapeutic standpoint. This is convincingly demonstrated by the diuretic
indacrinone
Indacrinone is a loop diuretic. It can be used in patients of gout with hypertension as an antihypertensive because it decreases reabsorption of uric acid, while other diuretics increase it.
Chirality and biological activity
Indacrinone is ...
.
The (R)-(+)-isomer, the eutomer, is responsible for the diuretic action and undesired uric acid retention, a side-effect common to many diuretics. The (S)-(-)-isomer, the distomer, acts as a uricosuric agent and thus antagonizes the side-effect caused by the (R)-isomer. A superficial examination of these facts might suggest the marketing of this product as a racemate (1:1 mixture of both enantiomers) to be desirable, since both enantiomers are complementing each other, but for optimal action, the ideal eutomer to distomer ratio for indacrinone has been determined to be 9:1. This is a classical case of a non-racemic drug. Alternatively, it is possible that in the body the distomer converts, at least in part, into the eutomer.
Calculation
One way the eudysmic ratio is computed is by dividing the
EC50 or the
IC50 of the eutomer by the same measurement of the distomer.
Whether one chooses to use the
EC50 or
IC50 depends on the drug in question.
Examples
*
Citalopram
Citalopram, sold under the brand name Celexa among others, is an antidepressant of the selective serotonin reuptake inhibitor (SSRI) class. It is used to treat major depressive disorder, obsessive compulsive disorder, panic disorder, and socia ...
is a case example of such a compound, and steps were taken to separate out the weaker enantiomer.
*
Thalidomide
Thalidomide, sold under the brand names Contergan and Thalomid among others, is a medication used to treat a number of cancers (including multiple myeloma), graft-versus-host disease, and a number of skin conditions including complications of ...
is a drug whose two enantiomers cause distinctly different effects from one another. The unforeseen
teratogenicity
Teratology is the study of abnormalities of physiological development in organisms during their life span. It is a sub-discipline in medical genetics which focuses on the classification of congenital abnormalities in dysmorphology. The related t ...
of the (R)-(+)-isomer caused it to become an important case study of stereochemistry in medicine. Although it is possible to chemically isolate just the desired (S)-(-)-isomer from the racemic mixture, the two enantiomers rapidly interconvert
in vivo
Studies that are ''in vivo'' (Latin for "within the living"; often not italicized in English) are those in which the effects of various biological entities are tested on whole, living organisms or cells, usually animals, including humans, and ...
; thus rendering their separation to be of little use.
*
Methorphan
Methorphan comes in two isomeric forms, each with differing pharmacology and effects:
* Dextromethorphan - An over-the-counter cough suppressant, as well as dissociative hallucinogen.
* Levomethorphan - A potent opioid analgesic that was ne ...
is another drug whose two enantiomers possess very different binding profiles, with the
L enantiomer being a potent
opioid
Opioids are substances that act on opioid receptors to produce morphine-like effects. Medically they are primarily used for pain relief, including anesthesia. Other medical uses include suppression of diarrhea, replacement therapy for opioid us ...
analgesic, and the
D enantiomer being a commonly used over-the-counter cough suppressant which acts as an NMDA-antagonist but possesses nearly no opioid activity. In the case of morphinan, the eudysmic ratio is preserved after metabolism as the
D and
L metabolites possess the same pharmacological targets as the corresponding methorphan enantiomers, but are considerably more potent than their parent compounds.
*
Amino acid
Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although hundreds of amino acids exist in nature, by far the most important are the alpha-amino acids, which comprise proteins. Only 22 alpha am ...
s are also a very interesting example of eudysmic ratio. Nearly all of the amino acids in the human body are called "L" amino acids; despite being chiral, the body almost exclusively creates and uses amino acids in this one configuration. D amino acids, the enantiomers - or "mirror images" - of the amino acids in the human body cannot be incorporated into proteins.
D-aspartate
Aspartic acid (symbol Asp or D; the ionic form is known as aspartate), is an α-amino acid that is used in the biosynthesis of proteins. Like all other amino acids, it contains an amino group and a carboxylic acid. Its α-amino group is in the pro ...
and
D-serine
Serine (symbol Ser or S) is an α-amino acid that is used in the biosynthesis of proteins. It contains an α-amino group (which is in the protonated − form under biological conditions), a carboxyl group (which is in the deprotonated − form ...
are two notable counterexamples, since they do not appear to ever be incorporated into proteins, but instead act individually as signalling molecules. However, mammals can metabolize significant amount of D amino acids by oxidizing them to
alpha-ketoacid
In organic chemistry, keto acids or ketoacids (also called oxo acids or oxoacids) are organic compounds that contain a carboxylic acid group () and a ketone group ().Franz Dietrich Klingler, Wolfgang Ebertz "Oxocarboxylic Acids" in Ullmann's ...
s (most of which are non-chiral) and then
transaminase
Transaminases or aminotransferases are enzymes that catalyze a transamination reaction between an amino acid and an α-keto acid. They are important in the synthesis of amino acids, which form proteins.
Function and mechanism
An amino acid co ...
s can create L amino acids. There are no reasons to believe that humans are exceptional, they have all required enzymes (
DDO,
DAO
Dao, Dão or DAO may refer to:
* Tao (Chinese: "The Way" 道), a philosophical concept
* Dao (Chinese sword) (刀), a type of Chinese sword
* Dao (Naga sword), a weapon and a tool of Naga people
People and language
* Yao people, a minority ethni ...
). Some common foods contain near-
racemic mixture
In chemistry, a racemic mixture, or racemate (), is one that has equal amounts of left- and right-handed enantiomers of a chiral molecule or salt. Racemic mixtures are rare in nature, but many compounds are produced industrially as racemates. ...
s of
amino acids
Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although hundreds of amino acids exist in nature, by far the most important are the alpha-amino acids, which comprise proteins. Only 22 alpha am ...
.
See also
*
Enantiopure drug An enantiopure drug is a pharmaceutical that is available in one specific enantiomeric form. Most biological molecules (proteins, sugars, etc.) are present in only one of many chiral forms, so different enantiomers of a chiral drug molecule bind di ...
References
{{reflist, 30em
Pharmacodynamics
Stereochemistry