Lecture 5: Drug-receptor stereochemistry Flashcards
Arnaldo Piutti
-1886 first observation that enantiomers can have different activity
-stereochemistry
L-asparagine
tasteless
D-asparagine
very sweet
Enantiomers
-nonsuperimposable mirror images
-identical pyshiochemical properties (size, solubility, ionization) except optical rotation
Enantiomer nomenclature
-R/S
- +/- (d/l)
-D/L
R/S system
-by absolute configuration
-3D only
-primary method for drugs
+/- (d/l) system
-by optical rotation
-experimentally determined
-dependent on solution condition
D/L system
-by relative configuration to glyceraldehyde
-obsolete used only for amino acids and sugars
L-amino acids
-all amino acids in proteins (except Gly)
-most are S except Cys which is R
Determination of R/S configuration
- determine priority of the groups attached to chiral carbon
- view molecule with group of lowest priority away
- clockwise vs counterclockwise order of the remaining groups
Cahn-Ingold-Prelog (CIP) priority rule
determines priority of groups attached to chiral carbon
Levorphanol
analgesic
Dextrorphan
antitussive
Levorphanol enantiomer
dextrorphan
Receptors
-biomolecules formed with chiral structural units
-ALL binding pockets are chiral
Easson-Stedman hypothesis (1933)
-the more potent enantiomer must be involved in a minimum of 3 intramolecular interactions with the receptor
R-epinephrine
endogenous hormone
S-epinephrine
much less vasopressor activity than R-epinephrine
N-methyldopamine
same vasopressor activity as S-epinephrine
Stereochemical interactions
-matters even before target binding affects:
-permeation by transporters
-nonspecific binding to serum proteins
-metabolism
Phases a drug encounters before reaching target
-membrane selectivity
-selective metabolism
-nonspecific receptors
-drug receptor
Racemic Mixtures
-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
Naproxen
-sold as pure enantiomer
-(S) active
-(R) liver poisoning
Stereoisomers
-molecule with more than one chiral center can have up to 2^n
-enantiomers and diastereomers
Diastereoisomers
not mirror image
Geometric isomers
-double bonds
-E/Z nomenclature
E/Z nomenclature
-E is trans
-Z is cis
What is the proper name of the propranolol stereoisomer shown below?
S-propranolol
Homologous Drugs
-different R/S notation
-same relative orientation of the relevant functional groups
-(R)-norepinephrine and (S)-propranolol
The structure of a stereoisomer of ibuprofen is shown below. What is the proper name of this stereoisomer?
R-ibuprofen
Which of the following is NOT affected by the stereochemistry of a drug?
-passive diffusion
Which of the following statements is correct about stereochemistry of drugs?
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.
Which of the following descriptions of enantiomers is incorrect?
They have different solubility in water.
