CNS Chem Flashcards

1
Q

Lipophilicity (log P)

A

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

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2
Q

The importance of pKa

A

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

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3
Q

Benzodiazepines – selective GABAA receptor agonists (SAR study)

A

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

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4
Q

Anxiolytics (metabolism)… Benzodiazepines

A
  • 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
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5
Q

Antidepressants

A
  • Tricyclic antidepressants (TCAs)
  • Serotonin specific re-uptake inhibitors (SSRIs)
  • Monoamine oxidase inhibitors (MAOIs)
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6
Q

Antidepressants (log P and pKa)

A
Tricyclic antidepressants (TCAs) – inhibit re-uptake of
norepinephrine and serotonin
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7
Q

Antidepressants (metabolism)…Tricyclic antidepressants (TCAs)

A

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

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8
Q

Antidepressants (log P and pKa)

A

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

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9
Q

Antidepressants (metabolism)

A

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

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10
Q

Antidepressants (log P and pKa)

A
  • Monoamine oxidase inhibitors (MAOIs) – prevent
    degradation of norepinephrine and 5-HT (in synapse)
  • phenelzine
  • MAOIs are used less frequently than TCAs & SSRIs
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11
Q

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

A

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

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12
Q

Antiepileptics, AEDs (log P and pKa)

A

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

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13
Q

Drugs for AD (log P and pKa)

A

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

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14
Q

Galantamine as a semi-synthetic drug example

A

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

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15
Q

Drugs for PD (log P and pKa)

A

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
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