Stereochemistry

The stereochemistry of both the receptor site & the drug molecule helps determine the nature & efficiency of the drug-receptor interaction. Isomers are 2 or more compounds, with the same molecular formula, but have different configurations. They usually differ in chemical, physical or pharmacological properties.

Stereoisomers can be divided into 3 main groups:

• Optical isomers,
• Geometric isomers,
• Conformational isomers.

I. Optical Isomers:

Contain at least 1 asymmetric, or chiral, carbon atom (a carbon atom which is covalently bonded to 4 different substituents). Each asymmetric carbon can exist in 1 of 2 non-superimposable isomeric forms.

The 2 enantiomers of 2-hydroxybutane. The chiral carbon is bonded to 4 different groups. The structures shown are mirror images that cannot be superimposed.

1. 1.     Enantiomers (Optical antipodes):

• Are optical isomers that are mirror images (have at least 1 asymmetric carbon), not superimposable.
• Enantiomers have identical physical & chemical properties except that one rotates the plane of polarized light in a clockwise direction (dextrorotatory, designated D or +) & the other in a counter-clockwise direction (levorotatory, designated L or -).
• An equal mixture of D and L enantiomers is called a racemic mixture & is optically inactive.
•  Enantiomers can have large differences in potency, receptor fit, biologic activity, transport & metabolism. E.g., levorphanol has narcotic, analgesic, & antitussive properties, whereas its mirror image, dextrorphanol, has only antitussive activity.
• Mutarotation: is a change in the optical rotation of a solution of an optically active compound (common in carbohydrate solutions).

H – C – OH

H – C – H

N

CH3

H

Dextro (+)

HO – C – H

H – C – H

N

CH3

H

Levo (-)

1. 2.     Diastereomers:

• Are stereoisomers, which are neither mirror images nor superimposable.
• A drug must have at least two chiral centers in order to exist in diastereomers.
• Unlike enantiomers, in which all stereochemical centers are opposite, diastereomers have some stereochemical centers that are identical & some that are opposite.
• Diastereomers possess different physicochemical properties &, thus, differ in properties, such as solubility, volatility, & melting points.
• Ephedrine has 2 assymetric centers & 4 isomers, there are 2 pairs of optical enantiomers:

                    i.      2 pairs are designated ephedrine (levo & dextro) (mirror images).

                  ii.      The 2 other pairs are designated pseudo-ephedrine (levo & dextro) (mirror images).

                iii.      However, ephedrine & pseudo-ephedrine are diasteriomers (not mirror images).

H – C – OH

CH3 – HN – C – H

CH3

Pseudo-ephedrine

H O– C – H

H – C –NH – CH3

CH3

Dextro (+)

Levo (+)

HO – C – H

CH3 – HN – C – H

CH3

Ephedrine

H – C – OH

H – C –NH – CH3

CH3

Dextro (+)

Levo (+)

1. 3.     Epimers:

• Are a special type of diastereomers because all epimers are also diastereomers; however, the opposite is not true.
• Epimers are compounds that are structurally identical in all respects except for the stereochemistry about one chiral center.
• The process of epimerization (in which the stereochemistry of one chiral center is inverted) is important in drug degradation & inactivation.

                    

 

II- Geometric Isomers (cis-trans isomers)

Occur as a result of restricted rotation around a chemical bond, owing to double bonds (or rigid ring systems) in the molecule.

• Cis-trans isomers are not mirror images & have different physicochemical properties & pharmacologic activity.
• Cis means that both 2 groups are fixed around the double bond so that they are both on the same side of the molecule. (Cis = Z).
• Trans means that both 2 groups are fixed around the double bond so that they are on opposite sides of the molecule. (Trans = E).
• Because the functional groups of these isomers are separated by different distances, they generally do not fit the same receptor equally well. E.g., cis-diethylstilbestrol has only 7% of the estrogenic activity of trans-diethylstilbestrol.

 

The presence of the double bond allows for the formation of cis & trans isomers

 

HOOC (CH2)7 CH

CH3 (CH2)7 CH

CH (CH2)7 COOH

CH3 (CH2)7 CH

 

             Oleic acid (Cis configuration – Z)                Eliadic acid (Trans configuration – E)

 

            CH₃                        CH₃                                              CH₃                             H

                          C = C                                                                           C = C

              H                          H                                                     H                          CH₃

    

    Cis 2 butene (Z)                                                                 Trans 2 butene (E)

 

III- Conformational Isomers  (Rotamers or Conformers)

• Are non-superimposable orientations of a molecule which result from the rotation of atoms about one or more single bonds.
  • Ethane has 2 conformational isomers:

H

H

H

H

H

H

Staggered

H

H

H

H

H

H

Eclipsed

• Cyclo-hexane exists in 2 conformers:

Boat

Chair

• Almost every drug can exist in more than one conformation, & this ability allows many drugs to bind to multiple receptors & receptor subtypes. E.g., the trans conformation of acetylcholine binds to the muscarinic receptor, whereas the gauche conformation binds to the nicotinic receptor.

 

The trans & gauche conformations of acetylcholine occur as a result of rotation about the carbon – carbon single bond.

          trans                                        gauche

 

 

IV- Bioisosteres

• Are molecules containing groups that are spatially & electronically equivalent &, thus, interchangeable without significantly altering the molecules’ physicochemical properties.
• Isosteric replacement of functional groups can increase potency, decrease side effects, separate biologic activities, & increase the duration of action by altering metabolism.
• Additionally, isosteric analogs may act antagonistically to the parent molecule.
  • Procainamide, an amide, has a longer duration of action than procaine, an ester, because of the isosteric replacement of the ester oxygen with a nitrogen atom.

                             

• Alloxanthine is an inhibitor of xanthine oxidase. It is also an isostere of xanthine, the normal substrate for the enzyme.

                                                 

CH2 CH2 CH2N

S

N

CH3

CH3

CH2 CH2 CH2N

S

O

CH3

CH3

Phenothiazine ring

Thioxanthene ring

Homologs: When 2 compounds differ only in the length of side chain.

CH2 CH2  N

S

N

CH3

CH3

CH2 CH2 CH2 N

S

N

CH3

CH3

N.B. Bioisosters & homologs are not optical isomers.

Tautomerism: Keto – Enol form (e.g. Uracil, purine / pyrimidine).