Lecture 5: Drug-receptor stereochemistry

Question 1

Arnaldo Piutti

Answer 1

-1886 first observation that enantiomers can have different activity
-stereochemistry

Question 2

L-asparagine

Answer 2

tasteless

Question 3

D-asparagine

Answer 3

very sweet

Question 4

Enantiomers

Answer 4

-nonsuperimposable mirror images
-identical pyshiochemical properties (size, solubility, ionization) except optical rotation

Question 5

Enantiomer nomenclature

Answer 5

-R/S
- +/- (d/l)
-D/L

Question 6

R/S system

Answer 6

-by absolute configuration
-3D only
-primary method for drugs

Question 7

+/- (d/l) system

Answer 7

-by optical rotation
-experimentally determined
-dependent on solution condition

Question 8

D/L system

Answer 8

-by relative configuration to glyceraldehyde
-obsolete used only for amino acids and sugars

Question 9

L-amino acids

Answer 9

-all amino acids in proteins (except Gly)
-most are S except Cys which is R

Question 10

Determination of R/S configuration

Answer 10

1. determine priority of the groups attached to chiral carbon
2. view molecule with group of lowest priority away
3. clockwise vs counterclockwise order of the remaining groups

Question 11

Cahn-Ingold-Prelog (CIP) priority rule

Answer 11

determines priority of groups attached to chiral carbon

Question 12

Levorphanol

Answer 12

analgesic

Question 13

Dextrorphan

Answer 13

antitussive

Question 14

Levorphanol enantiomer

Answer 14

dextrorphan

Question 15

Receptors

Answer 15

-biomolecules formed with chiral structural units
-ALL binding pockets are chiral

Question 16

Easson-Stedman hypothesis (1933)

Answer 16

-the more potent enantiomer must be involved in a minimum of 3 intramolecular interactions with the receptor

Question 17

R-epinephrine

Answer 17

endogenous hormone

Question 18

S-epinephrine

Answer 18

much less vasopressor activity than R-epinephrine

Question 19

N-methyldopamine

Answer 19

same vasopressor activity as S-epinephrine

Question 20

Stereochemical interactions

Answer 20

-matters even before target binding affects:
-permeation by transporters
-nonspecific binding to serum proteins
-metabolism

Question 21

Phases a drug encounters before reaching target

Answer 21

-membrane selectivity
-selective metabolism
-nonspecific receptors
-drug receptor

Question 22

Racemic Mixtures

Answer 22

-many drugs sold this way even though one enantiomer works
-costs too much to separate
-inactive enantiomer is usually inert
-NOT used if enantiomer shows bad side effects

Question 23

Naproxen

Answer 23

-sold as pure enantiomer
-(S) active
-(R) liver poisoning

Question 24

Stereoisomers

Answer 24

-molecule with more than one chiral center can have up to 2^n
-enantiomers and diastereomers

Question 25

Diastereoisomers

Answer 25

not mirror image

Question 26

Geometric isomers

Answer 26

-double bonds
-E/Z nomenclature

Question 27

E/Z nomenclature

Answer 27

-E is trans
-Z is cis

Question 28

What is the proper name of the propranolol stereoisomer shown below?

Answer 28

S-propranolol

Question 29

Homologous Drugs

Answer 29

-different R/S notation
-same relative orientation of the relevant functional groups
-(R)-norepinephrine and (S)-propranolol

Question 30

The structure of a stereoisomer of ibuprofen is shown below. What is the proper name of this stereoisomer?

Answer 30

R-ibuprofen

Question 31

Which of the following is NOT affected by the stereochemistry of a drug?

Answer 31

-passive diffusion

Question 32

Which of the following statements is correct about stereochemistry of drugs?

Answer 32

All the above:
-The enantiomer of a drug may have serious side effects.

-The enantiomer of a drug is not likely to have the same efficacy as the drug.

-If the enantiomer of a drug is inert, the racemic mixture can be used as a drug.

Question 33

Which of the following descriptions of enantiomers is incorrect?

Answer 33

They have different solubility in water.