CNS Chem

Question 1

Lipophilicity (log P)

Answer 1

Substituent hydrophobicity constant, π
§ Is a measure of how hydrophobic a substituent is, relative to hydrogen
§ It allows the partition coefficient, for a particular compound, to be calculated (rather than being measured experimentally)
§ A positive value = more hydrophobic than hydrogen
§ A negative value = less hydrophobic than hydrogen

Question 2

The importance of pKa

Answer 2

o Drug absorption is determined by solubility, molecular
weight and the degree of ionisation
o The local pH will dictate the degree of drug ionisation

Question 3

Benzodiazepines – selective GABAA receptor agonists (SAR study)

Answer 3

Diazepam
- Activity increases: when ring A is aromatic rather than a
heteroaromatic ring
- Activity increases: When position 7 contains an electronegative atom / group
- Activity increases: When position 2 has H-accepting C=O group
- Activity decreases: When position 4’ contains a substituent

Question 4

Anxiolytics (metabolism)… Benzodiazepines

Answer 4

• N-Demethylation at position N1 (replaces CH3 with H)
• In compounds with two aromatic rings, hydroxylation occurs preferentially in the more electron-rich ring, e.g. aromatic hydroxylation of diazepam occurs primarily in the more activated ring to give 4’-hydroxydiazepam
• Microsomal hydroxylation at C3 proceeds with remarkable stereoselectivity to yield oxazepam

Question 5

Antidepressants

Answer 5

• Tricyclic antidepressants (TCAs)
• Serotonin specific re-uptake inhibitors (SSRIs)
• Monoamine oxidase inhibitors (MAOIs)

Question 6

Antidepressants (log P and pKa)

Answer 6

Tricyclic antidepressants (TCAs) – inhibit re-uptake of
norepinephrine and serotonin

Question 7

Antidepressants (metabolism)…Tricyclic antidepressants (TCAs)

Answer 7

inhibit re-uptake of norepinephrine & serotonin
- amitriptyline
• Benzylic hydroxylation - oxidative metabolism at the 10 or 11 position, which generates E & Z isomers (due to 5-exo cyclic double bond).
• N-Demethylation produces nortriptyline

Question 8

Antidepressants (log P and pKa)

Answer 8

Serotonin specific re-uptake inhibitors (SSRIs) – inhibit re-uptake of serotonin without affecting the re-uptake of other neurotransmitters

Question 9

Antidepressants (metabolism)

Answer 9

Serotonin specific re-uptake inhibitors (SSRIs) – inhibit
re-uptake of serotonin without affecting the re-uptake of
other neurotransmitters
- fluoxetine
• N-Demethylation generates the major metabolite, which is as potent as the parent and more selective

Question 10

Antidepressants (log P and pKa)

Answer 10

• Monoamine oxidase inhibitors (MAOIs) – prevent
  degradation of norepinephrine and 5-HT (in synapse)
• phenelzine
• MAOIs are used less frequently than TCAs & SSRIs

Question 11

Antipsychotics (log P and pKa) e.g. Chlorpromazine

Answer 11

the first modern antipsychotic (1952). Useful as a sedative and in controlling patients with schizophrenia

Question 12

Antiepileptics, AEDs (log P and pKa)

Answer 12

e.g. phenytoin (PHT), carbamazepine (CBZ), valproate (VPA)

Question 13

Drugs for AD (log P and pKa)

Answer 13

Alzheimer’s disease results in low ACh, so one approach is to use AChE inhibitors
- tacrine, galantamine

Question 14

Galantamine as a semi-synthetic drug example

Answer 14

Galantamine - from European daffodils & snowdrops
• A tertiary alkaloid
• Beneficial to patients with mild Alzheimers Disease (AD)
- significant improvements in performance & attention
• Galantamine is extremely expensive ($50,000/kg)
• First successful synthesis of (-)-galantamine was in 1962 by Barton
• Also prepared by a stereospecific reduction of (-)-narwedine

Question 15

Drugs for PD (log P and pKa)

Answer 15

Parkinson’s disease is the second most common neurodegenerative disorder after AD. L-Dopa is the precursor to dopamine and alleviates symptoms (it is still the cornerstone of PD therapy)

• Dopamine, Too polar to cross BBB
• L-Dopa, Transported across BBB by AA transport system
• Carbidopa, L-AA decarboxylase inhibitor