Lecture 3 - Drug Absorption/Isomers Flashcards
What does the size of a molecule and its number of freely rotatable bonds effect?
- Activity
- Absorption
- Distribution
What are rotatable bonds?
Any single bond that is:
- not part of a ring
- not formed w/ a terminal atom
- not formed w/ an H atom
Are amide C-N bonds freely rotatable and why?
No b/c of resonance
Are amide enol keto tautomers freely rotatable and why?
No b/c of resonance
What do rotatable bonds have to do with crossing a membrane?
Usually a drug will have to be in a single conformation to cross a membrane
What do rotatable bonds have to do with binding to a receptor?
Usually drugs adopt one or a few conformations to bind to a receptor or transporter
What does more conformational freedom mean?
Less time spent in the right conformation for optimal absorption or binding
How do molecules w/ many freely rotatable bonds adopt a single conformation?
Must drop entropy significantly
What is Lipinski’s rule of fives?
A series of guidelines that determine if a drug can be absorbed orally
What are the rules of Lipinski’s rule of fives?
1) Molecular weight > 500
2) logP < 5
3) < 5 H-bond donors (sum of NH and OH)
4) < 10 H-bond acceptors (sum of lone pairs on N and O)
5) < 10 rotatable bonds
What can be concluded about polar drugs that don’t follow Lipinski’s rules?
- Not orally absorbed
- May be made into an injectable dosage form
What were Lipinski’s rules originally intended for and what are they used for now?
- Originally intended to be a way of predicting oral absorption
- Now used as a guide for industry to select candidate drugs
Does Lipinski’s rule of fives dictate pharmacologic activity?
Nope
What can be concluded about drugs on the market that don’t follow Lipinski’s rules?
They are taken up by transporters or other methods
Do all isomers have biological activity and why?
No, because normally only one configuration will bind to a receptor
Do all isomers have the same potency and toxicity?
No
Are all isomers metabolized the same?
No
Do isomers have the same molecular weight?
Yes
What are the 3 types of isomers?
1) Constitutional/structural/positional
2) Configurational
3) Conformational
What are constitutional isomers?
Have the same atomic composition but different bonding arrangements between atoms (ex: ortho, meta, para)
What are configurational isomers?
Have the same molecular formula and same bonds but the atoms are arranged differently in space with respect to each other
Can configurational isomers interconvert freely by bond rotation?
No
What are the 2 types of configurational isomers?
Optical and geometric
What are conformational isomers?
Different arrangements of atoms that result from rotation about sigma bonds
Can conformational isomers interconvert between isomeric forms?
Yes
When 4 different groups are bound to a carbon, how many distinct tetrahedral molecular forms (optical isomers) are possible?
2
What is another name for optical isomers?
Enantiomers
How many asymmetric centres can enantiomers have?
1 or more
Do enantiomers have identical physical and chemical properties?
Yes
What are the 2 important differences between enantiomers?
- Rotation of plane-polarized light
- Interaction w/ chiral environments
What does dextrorotatory mean?
Enantiomer rotates the plane to the right (clockwise)
What does levorotatory mean?
Enantiomer rotates the plane to the left (counterclockwise)
Can you determine the rotation of plane polarized light by inspection of a molecule’s structure?
No, it must be determined experimentally
Can you determine the configuration of atoms around an asymmetric carbon from the direction of rotation?
No
What is a racemic mixture?
A 50/50 mixture of each enantiomer
Do racemic mixtures rotate plane-polarized light?
No
Is it easier to produce a racemic mixture or a pure enantiomer?
Racemic mixture
For “n” asymmetric centres, how many configurational isomers are possible?
Up to 2^n
What are diastereomers?
Compounds w/ more than 1 asymmetric centre where the compounds are not mirror images and are not superimposable
What are meso structures?
2 structures with 2 identical asymmetric centres such that the mirror images are superimposable
Are meso structures chiral?
No
Do meso structures have a plane of symmetry?
Yes
Will both enantiomers of a drug bind to a receptor or enzyme?
Not usually
All amino acids are ___
L
What do D and L indicate?
Absolute configuration around an asymmetric carbon
Do D and L tell you anything about rotation of plane-polarized light?
No
How do you determine if an amino acid is D or L?
Whether the alpha H points left or right when the COOH group is up and NH2 is down
Structures of enantiomers are designated as ___ or ___
R or S
What are the steps to determine if an enantiomer is R or S?
- Give each group directly attached to the asymmetric carbon a priority based on atomic number
- When 2 directly attached atoms have the same priority, move to the next atom out to assign priority
- If a double bond is present, the attached double bond atom is counted twice
- Once all are assigned a priority, the lowest priority group is turned into the page
- An ark is drawn connecting the groups facing out from highest to lowest
- Clockwise = R; counterclockwise = S
Do R and S determine if an atom is d or l?
No
Are all amino acids either R or S?
Can be either
What does erythro mean?
When all H’s in a Fischer projection point in the same direction
What does threo mean?
When the H’s in a Fischer projection point in opposite directions
Can alkenes have geometric isomers?
Yes, if each carbon in the double bond has different substitutions
Is rotation around a double bond possible?
No
Do geometric isomers have the same chemical properties?
No
What do E and Z mean?
E = trans and Z = cis
How do you determine E and Z?
Priority is assigned to substituents on either carbon of a double bond, if the higher priority groups are on the same side it is Z and opposite sides is E
Are the bonds in a ring system always cis?
No, can be trans
Is eclipsed or staggered form higher energy?
Eclipsed
Is eclipsed or staggered form favoured and why?
Staggered because it is low energy
Do cyclohexane have any pi bonds?
No, all sigma
Why is the boat conformation less favourable?
It is in the fully eclipsed conformation
Why is the chair conformation more favourable?
It is staggered
Is cyclohexane always in the chair conformation?
No, inter-conversion between chair and boat is possible
What is favoured with respect to equatorial and axial substitutions?
- 2 equatorial substitutions of H to CH3 is more stable and favoured
- 1 equatorial and 1 axial substitution is less stable and not favoured
For substituted cyclohexanes, which is the most stable?
The one with the greatest number of equatorial groups
For cyclohexanes with bulky substitutions, which conformation is most favourable?
The one that allows the substitution to be equatorial
