Eudysmic ratio

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The eudysmic ratio (also spelled eudismic ratio) represents the difference in pharmacologic activity between the two enantiomers 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. Eudysmic ratio (ER) reflects the degree of enantioselectivity of the biological systems. [1] [2] For example, (S)-propranolol has ER = 130, meaning that (S)-propranolol is 130 times more active than its (R)-enantiomer. [3]

Contents

Terminology

The eutomer is the enantiomer having the desired pharmacological activity, [4] 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. [5]

A racemic mixture is an equal mixture of both enantiomers, which may be easier to manufacture than a single enantiomeric form.

Indacrinone Enantiomers Indacrinone Enantiomers.png
Indacrinone Enantiomers

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. [6] In some cases, the eudysmic ratio is so high, that it is desired to separate 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. [7]  

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. [8] [9] [10] [11] 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. [12] [13] Whether one chooses to use the EC50 or IC50 depends on the drug in question.

Examples

See also

References

  1. Ariëns, Everardus J. (1986). "Stereochemistry: A source of problems in medicinal chemistry" . Medicinal Research Reviews. 6 (4): 451–466. doi:10.1002/med.2610060404. ISSN   0198-6325. PMID   3534485. S2CID   36115871.
  2. Ariëns, E. J. (1984). "Stereochemistry, a basis for sophisticated nonsense in pharmacokinetics and clinical pharmacology" . European Journal of Clinical Pharmacology. 26 (6): 663–668. doi:10.1007/BF00541922. ISSN   0031-6970. PMID   6092093. S2CID   30916093.
  3. Sheldon, Roger A. (1993). Chirotechnology : industrial synthesis of optically active compounds. New York: Marcel Dekker. ISBN   0-8247-9143-6. OCLC   27897833.
  4. Wermuth CG, Ganellin CR, Lindber P, Mitscher LA (1998). "Glossary of Terms used in Medicinal Chemistry (IUPAC Recommendations 1998)". Pure Appl. Chem. 70 (5): 1129–1143. doi: 10.1351/pac199870051129 .
  5. Roth HJ, Müller CE, Folkers G (1998). Stereochemie und Arzneistoffe. Stuttgart: Wissenschaftliche Verlagsgesellschaft. pp. 80–82. ISBN   3-8047-1485-4.
  6. Ariëns EJ (1984). "Stereochemistry, a basis for sophisticated nonsense in pharmacokinetics and clinical pharmacology". European Journal of Clinical Pharmacology. 26 (6): 663–8. doi:10.1007/bf00541922. PMID   6092093. S2CID   30916093.
  7. Drayer, Dennis E (1986). "Pharmacodynamic and pharmacokinetic differences between drug enantiomers in humans: An overview" . Clinical Pharmacology and Therapeutics. 40 (2): 125–133. doi:10.1038/clpt.1986.150. ISSN   0009-9236. PMID   3731675. S2CID   33537650.
  8. Tobert, J A; Cirillo, V J; Hitzenberger, G; James, I; Pryor, J; Cook, T; Buntinx, A; Holmes, I B; Lutterbeck, P M (1981). "Enhancement of uricosuric properties of indacrinone by manipulation of the enantiomer ratio" . Clinical Pharmacology and Therapeutics. 29 (3): 344–350. doi:10.1038/clpt.1981.47. ISSN   0009-9236. PMID   7471605. S2CID   42650689.
  9. Ariëns, Everardus J. (1986). "Stereochemistry: A source of problems in medicinal chemistry" . Medicinal Research Reviews. 6 (4): 451–466. doi:10.1002/med.2610060404. ISSN   0198-6325. PMID   3534485. S2CID   36115871.
  10. "Stereoselectivity of pesticides: Biological and chemical problems edited by E.J. Ariëns, J. J. S. van Rensen and W. Welling. Elsevier Science Publishers, Amsterdam, 1988, pp. 544, US$ 171.00m" . European Journal of Medicinal Chemistry. 23 (5): 491. 1988. doi:10.1016/0223-5234(88)90153-5. ISSN   0223-5234.
  11. Williams, Kenneth M. (1991), Molecular Asymmetry and Its Pharmacological Consequences , Advances in Pharmacology, vol. 22, Elsevier, pp. 57–135, doi:10.1016/s1054-3589(08)60033-2, ISBN   978-0-12-032922-9, PMID   1958505 , retrieved 2021-05-15
  12. Lehmann FP (February 1978). "Stereoselectivity and affinity in molecular pharmacology. III. Structural aspects in the mode of action of natural and synthetic auxins". Chemico-Biological Interactions. 20 (2): 239–49. Bibcode:1978CBI....20..239L. doi:10.1016/0009-2797(78)90057-1. PMID   647843.
  13. Ariëns EJ (1991). "Racemic therapeutics--ethical and regulatory aspects". European Journal of Clinical Pharmacology. 41 (2): 89–93. doi:10.1007/BF00265897. PMID   1743252. S2CID   12768116.
  14. Eriksson T, Björkman S, Roth B, Fyge A, Höglund P (1995). "Stereospecific determination, chiral inversion in vitro and pharmacokinetics in humans of the enantiomers of thalidomide". Chirality. 7 (1): 44–52. doi:10.1002/chir.530070109. PMID   7702998.