Lec 9- drugs and synthetic intermediate (3) Flashcards
1
Q
Concept Homologue
A
- Example
- Phenyl ethyl amine as lead structure
- This can turn an agonist into an antagonist
2
Q
Gradual inversion of the activity in a homologous series
A
3
Q
Agonist to antagonist
A
- Assay, measured bioactivity: Blood pressure in vivo in cats
- R=H NA, BP = Increased
- R=Me Adrenaline BP= Increased
- R from Me to Ethyl reduction of activity
- R=Propyl, Ethyl + 1C, BP down, Optimisation of C3 side chain
- From n-propyl to isopropyl= antagonist
- Same for butyl
4
Q
Homologue
A
- Activity can go up or down
- Maximum, Minimum
- All mathematical curves possible
- Usually maximum activity, Binding activity to optimise
- SAR
5
Q
Affinity of GABAA antagonist for the GABAA receptor site
A
- NB- lower IC50 the better
- N=3- the lowest binding affinity, this suggests that N=3 is the right distance
6
Q
Spacer
A
- Related to homologue
- Variation of the length of connecting carbon chain between 2 sites of binding
- Heterocyclic template and carboxylic acid
- Aromatic interaction/Ionic binding interaction
- Very long chains can bind to other receptors which increase the side effect profile of the drug
7
Q
Example
Diazepam: homologue- spacer
A
- N-alkylation
- Spacer: Add CH2 group
8
Q
Concept Bioisosteres
A
- bioisosteres are chemical substituents or groups with similar physical or chemical properties which produce broadly similar biological properties to another chemical compound
- An atom is replaced by a group of atoms= non-classical bioisosterate modification
- If you can link in with the electrons= classical modification
9
Q
Classical Bioisotere
A
- Isoelectronic, same number of atoms
- Cyclohexyl- CH2 = NH => CH=N
- Can be aliphatic, cyclic and aromatic
10
Q
Non-classical bioisosteres
A
11
Q
Concept: Ring opening
A
12
Q
Concept: Ring closure
A
13
Q
Splitting of dused rings often yields drugs with similar activity, sometimes with improved solubility and/or less toxicity
A
