CNS Chem Flashcards
Lipophilicity (log P)
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
The importance of pKa
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
Benzodiazepines – selective GABAA receptor agonists (SAR study)
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
Anxiolytics (metabolism)… Benzodiazepines
- 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
Antidepressants
- Tricyclic antidepressants (TCAs)
- Serotonin specific re-uptake inhibitors (SSRIs)
- Monoamine oxidase inhibitors (MAOIs)
Antidepressants (log P and pKa)
Tricyclic antidepressants (TCAs) – inhibit re-uptake of norepinephrine and serotonin
Antidepressants (metabolism)…Tricyclic antidepressants (TCAs)
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
Antidepressants (log P and pKa)
Serotonin specific re-uptake inhibitors (SSRIs) – inhibit re-uptake of serotonin without affecting the re-uptake of other neurotransmitters
Antidepressants (metabolism)
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
Antidepressants (log P and pKa)
- Monoamine oxidase inhibitors (MAOIs) – prevent
degradation of norepinephrine and 5-HT (in synapse) - phenelzine
- MAOIs are used less frequently than TCAs & SSRIs
Antipsychotics (log P and pKa) e.g. Chlorpromazine
the first modern antipsychotic (1952). Useful as a sedative and in controlling patients with schizophrenia
Antiepileptics, AEDs (log P and pKa)
e.g. phenytoin (PHT), carbamazepine (CBZ), valproate (VPA)
Drugs for AD (log P and pKa)
Alzheimer’s disease results in low ACh, so one approach is to use AChE inhibitors
- tacrine, galantamine
Galantamine as a semi-synthetic drug example
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
Drugs for PD (log P and pKa)
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