D8 Drug Action • Stereochemistry: Geometrical isomerism • Stereochemistry: Chirality • Ring strain: The b-lactam ring in penicillin • Polarity: The increased potency of heroin
Geometrical isomerism • Carbon to carbon double bond Full name? • A ring where there is restricted rotation. The two different geometric isomers may have very biological different effects. • Diaminedichloroplatinium (II), Pt(NH3)2Cl2 has a cis- and a trans- isomer. • The cis- isomer of Pt(NH3)2Cl2 is highly effective in the treatment of testicular and ovarian cancers, as well as other forms of cancer. The trans-isomer trans- platin is not an effective anti-cancer drug.
Chirality • Chiral carbons have four different groups and may exist as mirror images, e.g. amino acids • Drug molecules that process a chiral carbon atom will exist in two different enantiomeric forms. For example thalidomide (neurosedyn) Where is the chiralcarbon?
Thalidomide • One of the thalidomide enantiomers alleviates the symptoms of morning sickness in pregnant woman; • The other enantiomer causes severe deformities in the limbs of the baby.
Ring strain • All penicillins contain a 4-membered beta-lactam ring. The ring contains 2 carbon atoms that are sp3hybridized, a nitrogen atom that is sp3hybridized, and a carbon atom that is sp2 hybridized. This structure is similar to the combination of two amino acids cysteine and valine. • Penicillin Cysteine Valine • Because of the restrictions of the ring, the normal bond angles of 109.5 and 120 are not able to be obtained, and so the ring becomes strained. This makes the amide highly reactive. The ring opens so that the penicillin can become covalently bonded to the enzyme that synthesizes the cell walls of the bacterium, thus blocking its action.
Polarity- the increased potency of diamorphine (heroin) compared to morphine • Morphine molecules contain two polar hydroxyl groups; in heroin, these molecules are replaced by ethanoate (acetate) groups. • These two ester groups make heroin much less polar than morphine and more soluble in lipids, which are non-polar. Heroin can thus easily penetrate the lipid-based blood/brain barrier. • Morphine Heroin Much less polar groups Polar groups
The blood-brainbarrier A mechanism that controls the passage of substances from the blood into the cerobrospinalfluid and thus into the brain and spinal cord. The blood-brain barrier (BBB) lets essential metabolites, such as oxygen and glucose, pass from the blood to the brain and central nervous system (CNS) but blocks most molecules that are more massive than about 500 daltons. This is a low mass in biomolecular terms and means that everything from hormones and neurotransmittersto viruses and bacteria are refused access to the brain by the BBB. It also means that many drugs, which would otherwise be capable of treating disorders of the CNS, are denied access to the very regions where they would be affective.