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The Role of Isomerism in Drug Action

Understand geometrical isomerism and chirality in drug action, focusing on the beta-lactam ring in penicillin and the potency differences between heroin and morphine.

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The Role of Isomerism in Drug Action

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  1. Drug Action (D8) Pages 425-427 Definitions Geometrical Isomerism Chirality Beta-lactam ring (Penicillin) Heroin

  2. Definitions • Isomerism: • The existence of two or more molecules having the same molecular formula, but with different bonding arrangements of atoms, or different orientation of their atoms in space • Stereo-isomerism: • Isomerism arising from differences in the shapes of molecules (includes geometric and optical isomerism) • Same molecular and structural formulas, but different arrangement of the atoms in space

  3. Definitions: Types of Stereo-Isomerism • Geometric Isomerism: • Occurs in alkenes (double bond:CNH2N) when there is restricted rotation around the C-C double bond. • It can also occur in ring system where there is restricted rotation about a C-C single bond • Optical Isomerism: • Typically occurs when a molecule has no plane of symmetry and can exist in left and right-handed, non-super imposable, mirror images. • The molecule must possess a chiral center (asymmetric) • Chiral: the carbon atom is attached to 4 or more different atoms or functional groups • Optical isomers rotate plane-polarized light

  4. Objective One: Explain the importance of geometrical isomerism in drug action • Physical Properties of Geometric Isomers • Different polarity (dipole movement changes) • Different boiling and melting points • Change in solubility • Chemical Properties of Geometric Isomers • Some properties are similar because the isomers have identical functional groups attached. • But, can have different pharmacological effects • Due to cis (same side) vs. trans (opposite) arrangements • Cis: 1,2-disubsituted alkenes with functional groups or atoms which are on the same side of the molecule • Trans: 1,2-disbustituted alkenes with functional groups or atoms on opposite sides of a double bond

  5. cis: same side trans: opposite side NH3 NH3 H3N Pt Cl Cl Pt Cl Cl NH3 Example: Cis vs. Trans • Pt(NH3)2Cl2 • cis-isomer: cisplatin • Anticaner, used in chemotherapy • trans-isomer: • Chemotherapeutically inactive

  6. DNA strand NH3 G Pt H3N G Example: Cis vs. Trans (continued) • Cisplatin • Square planar molecule, heavy metal complex • Can enter the nucleus of a cancerous cell • Cl atoms are replaced by bonds with guanine of the same DNA strand • Prevents replication, disrupts strand • Trans-isomer • Cl atoms are in the wrong position so cannot form bond with guanine

  7. H H C C C2H5 CH3 H3C H5C2 OH OH mirror Objective Two: Discuss the importance of chirality in drug action • Enantiomers • Non-super imposable mirror images (optical isomers) • Differ in their optical activity (aka their ability to rotate the plane of polarized light) • One isomer rotates the light clockwise • Other isomer rotates the light counterclockwise the same amount (equal and opposite) • Example

  8. Affect on Medicine • Racemic Mixtures • Equimolar mixtures of two enantiomers of the same compound • Because the rotation of plane-polarized light is equal but opposite ,the mixture is not optically active • Source of Drugs • Racemic mixtures not found in nature, so drugs from natural sources (natural or semi-synthetic) are single enantiomers • Synthesized drugs are usually racemic mixtures to reduce costs • No refining costs

  9. Racemic Mixtures in Medicine • Penicillin V (natural) • Synthetic enantiomer (not found in natural source) is not pharmacologically active • Ibuprofen (synthetic drug) • First enantiomer=analgesic and anti-inflammatory • Other enantiomer=no effects • Thalidomide (synthetic drug) • Both enantiomers=active • First=relieve morning sickness • Second=deformities in limbs, birth defects

  10. O C NH S CH3 R N CH3 R Group C O O OH beta-lactam ring carboxylic acid group Objective Three: Explain the importance of beta-lactam ring action penicillin • Structure of Penicillin • 3 structural groups: • R group, beta-lactam ring, carboxylic acid group

  11. Beta-lactam ring • Heteroatomic, 4-membered: • 1 Nitrogen, 3 Carbon • Square planar shape • Would prefer to be tetrahedral (has a non-bonding pair of electrons, nitrogen) • 90 degree angle puts the ring under chemical stress, increasing reactivity • Increased reactivity opens the ring

  12. Open Ring • Can covalently bond to transpeptidase • Enzyme responsible for the synthesis of bacterial cell walls • Blocks the action of transpeptidase • No bacterial growth is possible • Bacteria bursts with out the linkage between the cell walls • Penicillin can fight infections!

  13. Objective Four: Explain the increased potency of diamorphine (heroin) compared to morphine • Structural Differences • Heroin has same Carbon skeleton • Two OH groups replaced by CH3COO (ester) • Ester is less polar, more fat soluble, than OH. • More rapidly absorbed into the nonpolar central nervous system and brain • Heroin • Semisyntehtic narcotic • More potent, stronger painkiller • Highly addictive

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