Chirality of Drugs

  • Property of a compound whose molecules are not super imposable on their mirror images.
  •  Chirality  = Handedness.
  • two isomers are identical in physiochemical properties but different in their ability to rotate plane polarized light.
  •  Necessary condition for existence of enantiomers.

Significance of Chirality

  • Biological activity may reside in only one of the stereoisomer.
  • Stereoisomer’s may show essentially similar qualitative  and  quantitative activity.
  • Isomer may exhibit similar qualitatively but different quantitatively  activities.
  • Isomer may show distinct pharmacological activity.

Types of stereoisomers

  • Geometric isomers
  • Optical isomers
  • Because geometric isomers have different chemical and physical properties, they act differently as drugs in our bodies as well.

Example :

  • cis-platin  used for chemotherapy  – it can enter cancer cells and interact with DNA
  • Trans- platin  – not active

Optical Isomers

  • have a chiral center (the central carbon in an optical isomer with four bonds each attached to a different group.)
  • Molecule and mirror image cannot be superimposed into each other even after twisting and turning them.
  •   Identical physical and chemical properties
  • Enantiomer: another name for a molecule that is found in optical isomers. For example, ibuprofen has a two enantiomers, a left rotating enantiomer and a right rotating enantiomer.
  •    Dextrorotatory (“+” / “d” form) – clockwise direction.
  •    Levorotatory (“-“ / “l” form) – anti-clockwise direction.
  • Clockwise –  R (rectus).
  •  Anticlockwise –  S (sinister).
  • Racemic mixture: A mixture of 50% left rotating and 50% right rotating optical isomers

                 STEREOPHARMACOLOGY

  • Affinity of a drug for a specific receptor and its intrinsic activity are related to its chemical structure.
  • Drug – receptor interactions are stereo selective.
  • Minor changes in drug molecule structure. 
  •  Major changes in pharmacological properties.

Implication:

  • Biomolecules (sugars, amino acids, DNA, proteins, steroids) are chiral
  • Proteins are built from L-amino acids, which implies that enzymes – the catalysts of nature – are chiral
  • Also, receptors (drug, taste, biopharmaceuticals, agrochemicals) are chiral and the natural ligand to a receptor is often only one specific enantiomer
  • This is why mirror image molecules can have radically different activities (effectivity, toxicity, taste) in the body.
  • E.g. olfactory sensors are chiral – Different smell
  • In 2006 –
  • 80%  drugs approved by the FDA were chiral.
  • 75% single enantiomers.
  • FDA now requires information about the structure and activity of each isomer present in a racemic mixture of a new medication.

CHIRAL INVERSION

  • Unique metabolic pathway.
  •  Enzymatic or non-enzymatic.
  •  Involves unidirectional conversion of one enantiomeric form to another.                                   

                                                         R  →  S

CHIRAL SWITCH

  • Development of a single enantiomer from a previously marketed racemate.
  •  Resulted in a number of agents being re-marketed as  chiral drugs.
  •  Same or similar therapeutic indications.
  • Novel indications for old compounds.

THALIDOMIDE

  •   One asymmetric carbon atom, exists as 2 enantiomers
  • S-Enantiomer → sedative
  • R-Enantiomer ® Teratogen à Phocomelia

 S-Amlodipine is effective at half the dose of racemate           

  

ADVANTAGES OF CHIRAL DRUGS

  • Chiral drug is a single agent instead of a mixture of two distinct drugs.
  •  Simplifies the interpretation of the Basic Pharmacology.
  •  Greater selectivity for their biological  targets improved therapeutic indices and reduced adverse effects.
  •  Longer or shorter duration of action –  more appropriate dosing frequency.
  •  Decreased inter individual variability.
  • SOME DRUGS ARE BETTER AS RACEMATES – b  BLOCKERS

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