Anxiolytics/Antidepressants Flashcards
Serotonin Receptor, an important receptor in central nervous system (CNS). How many types and subtypes are there ?
7 types (5-HT1 - 5HT7) and 14 subtypes
Which receptor are G-Protein-coupled receptors ?
All of them except 5-HT3
What are the three subtypes of 5-HT2 receptor ?
5-HT2a, 5-HT2b and 5-HT2c
Which of these subtypes is thought to be involved in anxiety ?
5-HT2c receptor thought to be involved in anxiety
What is mCPP ?
mCPP is an agonist with some selectivity for 5-HT2c receptor causes anxiety
What may be useful in treating anxiety in relation to the receptors ?
Antagonist with selectivity for 5-HT2c receptor may be useful in treating anxiety
Give a bit more information about Serotonin ?
- Serotonin is a neurotransmitter
- Abnormal levels of serotonin are related to various disorders (e.g. anxiety, depression, migraine)
- Indole ring system is present
Briefly explain SSRIs (selective serotonin reuptake inhibitors)?
- Anxiety, OCD, eating disorders
- Prevent reuptake of serotonin
What is the aims of drug design ?
- Selectivity for 5-HT2c receptor receptor
- Selectivity over 5-HT2a and 5-HT and 5-HT2b
- Resistance to drug metabolism
- No effect on metabolic enzymes (drug-drug interactions)
- Aqueous solubility
- Non-sedating
Briefly explain Lead Compound ?
- Produced by Lilly Pharmaceuticals
- Serotonin antagonist
- Insoluble in water
Explain transition from From Lead Compound to SB 200646 ?
- Substituents removed from indole ring (simplification)
- Pyridine ring introduced (ring variation)
- Pyridine ring more polar - increases water solubility
- Urea link at optimum positions for both ring systems
- First selective 5-HT2b/c antagonist
- 50-fold selectivity over 5-2HT2a receptor
- Modest in vitro activity
- Some oral activity in vivo
Explain transition from SB 200646 to SB 206553 ?
- Rigidification limits number of possible conformations
- Rigidify structure such that active conformation still allowed
- Increased chance of active conformation being present
- 10-fold increase of 10-fold increase of in vitro affinity
- 160-fold selectivity over 5-HT160-fold selectivity over 5-HT2a receptor
- 4-fold increase of 4-fold increase of in vivo activity
Explain transition from SB 206553 to SB 221284 ?
- Best balance of affinity vs selectivity
- Potent inhibitor of 5-HT2b and 5-HT2c receptors
- Good selectivity over 5-HT2a receptor
- Inhibits cytochrome P450 enzymes
- Pyridine N is responsible for inhibiting cyt P450 enzymes
Explain transition from SB 221284 to SB 228357 ?
Structure II:
- Pyridine ring is more polar leading to increased water solubility
- 10-fold increase in affinity due to additional binding interactions
- Lower selectivity between 5-HT2c and 5-HT2a receptors
Structure III:
- Selectivity is recovered by adding a methyl substituent
- Slightly increased affinity for the 5-HT2c receptor
- Moderate oral activity
- Slight drop in cytochrome P450 inhibition
Explain transition SB 228357 to SB 243213 ?
- Methoxy group is replaced with a methyl group
- Less liable to metabolism
- Good profile of affinity, activity and selectivity
- Negligible cytochrome P450 activity
- Entered phase I clinical trials as a non-sedating antidepressant / anxiolytic
