Stereoselectivity in drugs

Question 1

Contergan scandal

Answer 1

Thalidomide. Sedative for pregnant women. Teratogenic: stillbirths, severe developmental abnormalities.

R-enantiomer > sedative effect, S-enantiomer > teratogenic effect

Question 2

Chirality, chiral center

Answer 2

Asymmetry > molecule cannot be superimposed onto mirror image.
Chiral centre: atom with altogether differing substituents (asymmetric atom).

Question 3

No. of steroisomers

Answer 3

= 2^n

n=number of chiral centers

Question 4

Enantiomer, racemate, diastereomer

Answer 4

Enantiomer: non-superimposable mirror images of each other > identical physiochemical properties.
Racemate: equimolar mixture of both enantiomers.
Diastereomer: not mirror images of each other > diff physiochemical properties

(Epimer: different configuration at only one chiral centre)

Question 5

Cahn-Ingolf-Prelog system

Answer 5

1. Determine priorities of atoms directly linked to chiral centre based on higher atomic number (H is always lowest priority)
2. If the same, consider second atoms away from chiral centre
3. Rotate molecule so that the group with the lowest priority is pointed away from the observer
4. Follow order from highest to lowest priority
   R for clockwise, S for counterclockwise

Question 6

Optical activity

Answer 6

Enantiomer rotates plane-polarized light to right (+/d) or left (-/l).
Polarimeter

Question 7

Advantages of enantiopure drugs

Answer 7

Increased efficacy (lower dose required), increased selectivity (less adverse effects), less drug interactions, simples pharmacokinetic and -dynamic profiles (more predictable)

Question 8

Racemic drugs

Answer 8

Enantiomers have own pharmacological activities that can be different (more: eutomer, less: distomer). Majority of chiral clinically used drugs.
Some enantiopure durgs may undergo chiral inversion/racemisation in vivo.

Question 9

Stereoselectivity in receptor binding: ketamine, salbutamol, beta-adrenergic receptor agonsts, NSAIDs

Answer 9

(S) ketamine has higher affinity and less undesired effects
(R) Salbutamol dilates airway smooth muscles (S contracts)
Beta-adrenergic receptor agonists: only - is active
NSAIDs: only + is active

Question 10

Stereoselectivity in pharmacokinetic processes

Answer 10

Enzymatic metbolism

Drug transport

Question 11

Warfarin metabolism

Answer 11

Anticoagulant.
S: eutomer, hydroxylysed by CYP2C9
R: hydoxylysed by CYP1A2 or CYP3A4

Question 12

Vmax, Km

Answer 12

Vmax: maximal activity (eg max transport activity)
Km: substrate conc at half of Vmax (Michaelis-Metnteen constant)

Question 13

Fenoterol uptake

Answer 13

R: by OCT1 (organic cation transporter) in liver
S: by OCT2 in kidney > excretion

Enantiomers occupy different binding sites in OCT1 but same binding site in OCT2