Lec 5 LOs

Question 1

how do you identify chiral centers from drug structures?

Answer 1

• have 4 different substituents on chiral carbon
• most drugs have chiral carbons and all receptors do

Question 2

Explain the differences between R/S, d/l, D/L nomenclature systems.

Answer 2

R/S
-by absolute configuration
- requires 3D arrangement for groups
- primary method for drugs
d/l & +/-
- experimentally determined
- optical rotation
- dependent on solution condition
D/L
- by relative configuration to glyceraldehyde
- obsolete; only for amino acids and sugars
- amino acids in proteins (except Gly) are all L-amino acids; most are S, but Cys is R

Question 3

Determine R/S and E/Z notations for drugs from their structures.

Answer 3

R/S
- determine priority of groups
- put lowest away
- determine in counterclockwise or clockwise based on priority rule
E/Z
- cis and trans
- cis is Z and means same side
- trans is E and means opposite sides

Question 4

Explain why drug enantiomers have different biological properties.

Answer 4

they have different properties based on the chiral carbons
- Arnold Piutti made the observation
- not superimposable and miror images
- different configurations can lead to many different properties such as optimal rotation

Question 5

Explain how the absolute stereochemistry of a molecule can influence receptor binding.

Answer 5

it matters due to interactions with various proteins
– metabolism
– permeation by transporters
– nonspecific binding to serum proteins
- they can have different R/S and same orientation but different properties

Question 6

List factors other than receptor binding that result in different biological properties of drug enantiomers.

Answer 6

• optical rotation
• metabolism
  – permeation by transporters
  – nonspecific binding to serum proteins
  —-> pharmacology, pharmacokinetics, metabolism, toxicity, immune response

Question 7

Explain the potential issues of racemic mixtures as drugs.

Answer 7

most drugs are sold as racemic mixtures because separating them is difficult and costly
–> ibuprofen
- although if the inactive enantiomer has serious side effects, it must be sold as the pure enantiomer instead
–> naproxen; other form leads to liver poisoning (R)

Question 8

When a pair of stereoisomers are given, determine whether they are enantiomers, diastereomers, or geometric isomers.

Answer 8

Enantiomers: a pair of stereoisomers non-superimposable mirror images
–> Ex: 1s,2r and 1r,2s
—— changes both chiral carbons
Diasteromers: a pair of stereoisomers that are not mirror images
–> Ex: 1s,2r and 1s,2s
—- only changes 1 chiral carbon
Geometric Isomers: are molecules with double bonds
– E/Z
—- Cis is Z and same
—- trans is E and different