Stereochemistry

Stereochemistry

1. Stereochemistry Qudsia Rehaman 606 Mutayyba Fatima 608

2. Stereochemistry Stereochemistry is defined as the study of the three-dimensional structure of molecules. OR A branch of chemistry that deals with the spatial arrangement of atoms and groups in molecules.

3. Stereoisomers Stereoisomers are molecules that contain the same number and kinds of atoms, the same arrangement of bonds, but different three-dimensional structures; in other words, they only differ in the three-dimensional arrangement of atoms in space.

4. Geometric isomerism Geometrical isomerism is a form of stereoisomerism describing the orientation of functional groups within a molecule. When two substituents of higher priority are on the same side of the double bond, this isomer is given the designation of cis or Z . When the substituents are on opposite sides, the designation is trans or E .

5. Example: The histamine H1-receptor antagonist triprolidine . The E-isomer of triprolidine is more active both in vitro and in vivo, indicating that the distance between the pyridine and pyrrolidine rings is critical for binding to the receptor.

6. Enantiomers Enantiomers are pairs of molecules for which the three-dimensional arrangement of atoms represents nonsuperimposable mirror images.

7. Examples

8. Examples R forms – therapeutically active (sedation) S forms _ teratogenic

9. Diastereoisomers Diastereoisomers represent all of the other stereoisomeric compounds that are not enantiomers . Thus, the term “ diastereoisomer ” includes compounds that contain double bonds (geometric isomers) and ring systems.

10. Diastereoisomers

11. PHARMACOKINETIC & PHARMACODYNAMIC STEREOSELECTIVITY Many drugs used in clinical practice contain one or more chiral centers . These chiral drugs are often used therapeutically either as pure stereoisomers or as a racemic mixture. The three dimensional interaction of two enantiomers with a macromolecule, such as an enzyme or receptor, to form diastereomeric complexes may result in chiral recognition and significant differences in pharmacokinetic processes as well as the pharmacodynamics

12. PK parameter Examples Absorption L- Methotrexate is better absorbed than D Methotrexate . Vol. of distribution S- Warfarin has lower Vd than R- Warfarin . Levoceterizine has smaller Vd than its dextroisomer . Metabolism S- warfarin is more potent and metabolized by ring oxidation while R- Warfarin is less potent and metabolized by side chain reduction and have delayed metabolism. Half-life S- warfarin = 32 hours; R- warfarin = 54 hours

13. Stereochemistry and Biological Activity Easson – Stedman hypothesis In 1886, Piutti ; reported different physiologic actions for the enantiomers of asparagine , (+) asparagine having sweet taste and (-) asparagine a bland one. This was one of the earliest observation that enantiomers can exhibit differences in biological action. In 1933, Easson -Stedman reported that differences in biological activity between enantiomers resulted from selective reactivity of one enantiomer with its receptor. They postulated that such interactions require minimum three- point fit to receptor. If the molecule is unable to properly fit into the receptor and , therefore , cannot ‘trigger’ the action.

14. 1)Pharmacological actions : Quinine - antimalarial property quinidine (d-isomer) - antiarrhythmic l sotalol - β blocking action d sotalol has antiarrhythmic action.

15. 2)Therapeutic and adverse effects R thalidomide - sedative S thalidomide causes teratogenic effect. D- ethambutol - to treat TB L ethambutol causes blindness.

16. 3) Efficacy S (-) carvedilol is 100 times more potent as β blocker than R (-) carvedilol . ( α receptor blocking action is equipotent) S timolol is more potent β receptor antagonist than R timolol but both reduce intra ocular tension to same extent.

17. 4) Drug interaction : 2 stereoisomers can compete for binding to the same receptor. Eg . S methadone antagonizes respiratory depressant action of R methadone.

18. If the 2 isomers are agonist & antagonist racemic mixture acts as partial agonist Eg . Picendol ( Opioid analgesic drug): (+) (3S, 4R) enantiomer - pure agonist (-) (3R, 4S) enantiomer - pure antagonist (+) (3RS, 4RS) racemic mixture - partial agonist

19. References: Pharmacological Significance of Stereoisomerism.. Journal of Mahatma Gandhi Institute of Medical Sciences. 15. 21-26. 5. Scott, A. K. (1990 ). Stereoisomers in Clinical Pharmacology. Drug Information Journal , 24 (1), 121–123 Foye’s principles of medicinal chemistry