Log P

Question 1

What is the TRUE partition coefficient?

Answer 1

The partition coefficient of unionised drug

P(TRUE)

Question 2

What is the main importance of the partition coefficient?

Answer 2

• can be used to predict the absorption, distribution, and drug elimination within the body

Question 3

What is Structural-Activity Relations?

Answer 3

• the partition coefficient is used in mathematical expressions to relate the biological activity of a drug to its physical and chemical properties

Question 4

Define the Hansch-Fujita parameters (π).

Answer 4

• these describe the contribution of various functional groups to the lipophilicity of a compound

Question 5

What are the hydrophobic functional groups for the Hansch-Fujita hydrophobic parameter (+π)?

Answer 5

• aromatic hydrocarbons
• aliphatic hydrocarbons
• halogens

Question 6

What effects does a predominance if +π groups have?

Answer 6

• leads to an increase in partition coefficient

- makes the molecule more lipid soluble and better able to pass through the lipid membranes

Question 7

What are the hydrophilic (polar) functional groups for the Hansch-Fujita hydrophilic parameters (-π)?

Answer 7

• hydroxyl groups
• carboxylate groups
• amines
• ether
• amide

Question 8

What effects does predominance of -π groups have?

Answer 8

• leads to a decrease in partition coefficient

- makes the molecule less lipid soluble and less able to pass through the lipid membranes.

Question 9

Define the partition coefficient.

Answer 9

• a constant
• it is the ratio of concentration of compound in organic phase to the concentration in aqueous phase at equilibrium
• P = Corg/Caq

Question 10

Describe forced acid diuresis.

Answer 10

• basic drugs are best reabsorbed from alkaline urine
• if the drug taken in overdose is a weak base forced acid diuresis is carried out by administering ammonium chloride or ascorbic acid

Question 11

Describe forced base diuresis.

Answer 11

• acidic drugs is best reabsorbed from acidic urine

- if the drug taken in overdose is a weak acid forced base diuresis is carried out by administering sodium bicarbonate

Question 12

What is Wallace’s rule?

Answer 12

%C-G and %A-T base pair content predicts temperature at which DNA duplex separates into strands (Tm)

• adding a C-G pair to a DNA double helix will raise Tm by 4K
• adding an A-T pair raises Tm by 2K

Question 13

What type of intermolecular interaction is involved with aromatic rings packing together?

Answer 13

• van der Waals interactions

- called π-π stacking

Question 14

What are three other aromatic ring packing orientations?

Answer 14

• parallel
• T-shaped
• parallel displaced

Question 15

What are the water effects on drug-receptor binding of non-polar molecules and subsequent what is the hydrophobic effect?

Answer 15

• on binding ligand and receptor lose unfavourable interaction with water
• hydrophobic effect - what is energetically happier when it’s H-bonding network is not disrupted by the non-polar surfaces of a ligand

Question 16

What are the water effects on drug-receptor binding of polar molecules?

Answer 16

• on binding ligand and receptor lose some favourable interaction with water
• cancels to some extent favourable ligand-receptor interactions formed in binding

Question 17

Define the term conformation.

Answer 17

• the different possible arrangements in space of the atoms in a molecule that are interconvertible by rotation about single bonds

Question 18

Why is fully eclipsed (SYN) less stable than eclipsed?

Answer 18

• torsional strain is due to PITZER strain plus steric strain
• steric repulsion between groups in close proximity
• steric strain is at a maximum in fully eclipsed (SYN) conformations
• steric strain increases with the increasing size of the group

Question 19

When choosing between developing a drug as a single enantiomer or as a racemate what properties must be considered?

Answer 19

A) pharmacological activity 
B) toxicity
C) metabolism 
D) chemistry
E) economics 
F) clinical trial results

Question 20

What are the EEC regulations for the registration of chiral drugs?

Answer 20

• stereochemical form intended must be specified
• properties A)-F) considered for both enantiomers
• information on the separation of the enantiomers provided
• information on the interconvertible rates of the enantiomers provided

Question 21

What are the current trends in drug development?

Answer 21

• develop a single enantiomer because it is a cleaner drug
• concerns over stereochemistry ads cost/time
  
  • ## avoid developing drugs with a chiral centre

Question 22

What is racemic switch chemistry?

Answer 22

• if a drug is currently marketed as the racemate then it’s patent can be extended by redeveloping it as a single enantiomer

Question 23

What do stereoisomers have different biological activity?

Answer 23

• drugs undergo:
  
  • active transport
  • interactions with enzymes/receptors to give activity
  • metabolism
• all these require binding to proteins:
  
  • made up of L-amino acids
  • binding site is chiral
  • stereoisomers of drugs bind in different ways

Question 24

What activity do the different stereoisomers of Thalidomide exert?

Answer 24

• (R)- enantiomer is a sedative

- (S)- enantiomer is a teratogen

Question 25

Describe the case study of propanolol.

Answer 25

• initially developed as a racemate
• it is a β-blocker
• used to treat heart arrhythmias
• S(-) enantiomer is the β-blocker
• R(+) enantiomer is a contraceptive
• now marketed as S(-) enantiomer

Question 26

Describe the case study of tamoxifen.

Answer 26

• treats oestrogen-dependent breast cancer
• Z is anti-oestrogenic
• E is oestrogenic: promotes tumour formation