PHRM 82400: Exam 1 - Lecture 5: Drug-Receptor Interaction and Stereochemistry

what are enantiomers?

stereoisomers that are mirror images of one another

what are the characteristics of enantiomers?

- not superimposable on one another

- have one or more chiral centers

- have identical physicochemical properties except optical rotation

- size, solubility, ionization, hydrophobicity, etc.

what are the characteristics of the R/S system?

- by absolute configuration

- requires the three-dimensional arrangement of the groups

- primary method for drugs

what are the characteristics of the +/- system?

- by optical rotation

- experimentally determined

- dependent on the solution condition

what are the characteristics of the d/l system?

- by the relative configuration to glyceraldehyde

- obsolete; used only for amino acids and sugars

- amino acids in proteins (except gly) are all l-amino acids; most of them are S, but Cys is R

how is R/S configuration determined?

1. determine the priority of the groups attached to the chiral carbon using Cahn-Ingold-Prelog (CIP) priority rule

2. view the molecule with the group of lowest priority away

3. consider the clockwise of counterclockwise order of the priority of the three remaining groups

enantiomers of a drug frequently show __________

strikingly different biological activities

what is the easson-stedman hypothesis?

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

what is the relationship between receptors and chirality?

- receptors are biomolecules that are formed with chiral structural units

- binding pockets of receptors are chiral

R-epinephrine is the __________

endogenous hormone

S-epinephrine has a much less _________ than R-epinephrine

vasopressor activity

how does stereochemistry matter even before target binding due to interaction with various proteins in the body?

- permeation by transporters

- nonspecific binding to serum proteins

- metabolism

what are the phases in which a drug can encounter prior to reaching the biologic target?

drug dose -> membrane selectivity -> selective metabolism -> nonspecific receptors, site of loss -> drug receptor -> desired response

why are many drugs sold as a racemic mixture (racemate) even though only one enantiomer has the biological activity?

- separation of enantiomers are difficult and costly

- the inactive enantiomer is physiologically inert in many cases

if the inactive enantiomer shows significant adverse side effects, the racemic mixture (should or should not) be used as a drug

should not

when a molecule has more than one chiral centers, how many stereoisomers are possible?

more than two

- enantiomers

- diastereomers

what is the definition of enantiomers?

a pair of the stereoisomers that are non-superimposable mirror images

what is the definition of diastereomers?

a pair of the stereoisomers that are not mirror images

molecules with double bonds may have __________

geometric isomers

- E/Z nomenclature

in many instances, two molecules can have __________ as designated by the CIP system, but the __________ of the functional groups relevant for biologic activity

different R/S notation; same relative orientation

- two drugs that bind to the same binding pocket may have different R/S notation by the CIP system