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Medicinal Chemistry 3 > Exam #02 (Antipsychotics) > Flashcards

Exam #02 (Antipsychotics) Flashcards

1
Q

Why is schizophrenia thought to be a paradoxical disease?

A

B/c there are positive and negative symptoms arising from excess DA and not enough DA, respectively

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2
Q

Positive symptoms of schizophrenia arise from excess DA in what tract of the brain?

A

mesolimbic tract

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3
Q

Negative symptoms of schizophrenia arise from reduced DA in what tract of the brain?

A

mesocortical tract

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4
Q

List the (3) positive symptoms of schizophrenia.

A
  1. Hallucinations
  2. Delusions
  3. Disorganized thinking
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5
Q

List the (3) negative symptoms of schizophrenia.

A
  1. Blunted affect
  2. Emotional withdrawal
  3. Poor rapport
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6
Q

Cognitive symptoms may result from INCREASED/DECREASED dopamine in the medial prefrontal cortex?

A

DECREASED

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7
Q

What (4) NT are implicated in schizophrenia?

A
  1. DA
  2. Glutamate
  3. Serotonin
  4. GABA
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8
Q

What is the difference between typical antipsychotic and atypical antipsychotic drugs? Indicate MOA and SE profile

A

Typical Antipsychotics
MOA: DA antagonists (D2)
SE: primary side effects are extrapyramidal side effects (EPS) which are movement abnormalities

Atypical antipsychotics
MOA: primarily 5-HT2A antagonism but can also have some DA antagonism
SE: reduced or no EPS (b/c less D2 antagonism) but significant increase in other side effects

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9
Q

True or False - most antipsychotic drugs today treat positive symptoms of schizophrenia?

A

True

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10
Q

What 2 drugs led to the DA hypothesis of schizophrenia? What is the DA hypothesis?

A
  1. Chlorpromazine - DA antagonist
  2. Reserpine - depletes synaptic DA

Modulating DA may Tx schizophrenia

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11
Q

What would a “perfect” DA-based antipsychotic look like (indicate MOA in specific areas of brain)?

A
  1. Drug would act as a DA antagonist in mesolimbic neurons where excess DA is

AND

  1. Drug would act as a DA agonist in the mesocortical, limbic, and prefrontal cortex neurons where reduced DA is

AND

  1. Drug would have no effect on nigrostriatal neurons
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12
Q

What is the key structural feature regarding the SAR of Phenothiazines?

A

The affinity to D2 receptor is determined by how easily the basic amine can fold over and lie over the ring containing the substituent. This is the conformation required to make it a D2 antagonist

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13
Q

What helps keep the Nitrogen up over the aromatic ring in a phenothiazine drug?

A

the electron-withdrawing group

When the basic amine folds up over the aromatic ring, the lone pair of electrons from the basic amine dissociates and that electron density is pulled away from the ring by the electron withdrawing group stabilizing the basic amine above the ring and maintaining D2 antagonist activity

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14
Q

True or False - the basic amine of phenothiazines has significant structural tolerance and can be changed to modify ADME properties?

A

True

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15
Q

Identify what antipsychotic group the following drug is from:

Triflupromazine (Vesprin)

A

Phenothiazine

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16
Q

Identify what antipsychotic group the following drug is from:

Thioridazine (Mellaril)

A

Phenothiazine

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17
Q

Identify what antipsychotic group the following drug is from:

Mesorindazine (Serentil)

A

Phenothiazine

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18
Q

Identify what antipsychotic group the following drug is from:

Prochlorperazine (Compazine)

A

Phenothiazine

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19
Q

Identify what antipsychotic group the following drug is from:

Perphenazine (Trilafon)

A

Phenothiazine

20
Q

Would a phenothiazine antipsychotic with anticholinergic SE be MORE or LESS likely to cause EPS (extrapyramidal SE)?

A

Less likely

EPS liabilities are less when strong anticholinergic effects are present

21
Q

True or False - anticholinergic activity of phenothiazine antipsychotics counter whatever changes occur in the substantia nigra that cause the EPS?

A

True

22
Q

Phenothiazine antipsychotics sedative effect is a result of blocking which receptor type?

A

H1 antagonism

23
Q

Phenothiazine antipsychotics HYPOtensive effects is a result of blocking which receptor type?

A

alpha-1 antagonism

24
Q

What does the S in thioxanthenes and phenothiazines mimic that contribute to their effectiveness?

A

S mimics the 3-OH of dopamine

25
Q

The optimal chain length (carbons) that optimizes the interaction of basic nitrogen with an electron poor ring for a Phenothiazine is?

A

3-carbons

26
Q

Name a structural difference between phenothiazines and thioxanthenes?

How are they different in terms of metabolism?

A

phenothiazines have a S and N in the middle ring, while thioxanthenes have only a S in the middle ring

Phenothiazine rings can be hydroxylated but Thioxanthene rings cannot

27
Q

True or False - phenothiazines are extensively metabolized and give several active and inactive metabolites?

A

True

28
Q

What is the most active metabolite of a phenothiazine?

A

7-hydroxy metabolite

29
Q

What are (3) essential SAR of Butyrophenones?

A
  1. 4 carbon chain
  2. “phenone”
  3. substituted or unsubstituted aryl
30
Q

Which group of antipsychotics are Haloperidol (Haldol) and Droperidol (Inapsine) from?

A

Butyrophenones

31
Q

2nd generation Butyrophenones replaced a ketone with an additional phenyl group. How did this affect its activity?

A

2nd generation Butyrophenones are potent D2 antagonists, potent 5-HT2A antagonists with less EPS than 1st generation

32
Q

Name (1) 2nd generation Butyrophenone.

A

Pimozide (Orap)

33
Q

Name (9) SE of typical antipsychotic drugs?

A
  1. EPS (movement disorders)***
  2. neuroleptic malignant syndrome
  3. sedation (from H1 antagonism)
  4. weight gain
  5. dyslipidemia
  6. hyperprolactinemia
  7. DM
  8. prolonged QTc
    9 CV effects

***EPS - inability to initiate movement or inability to remain motionless

34
Q

How are EPS treated?

A

with anticholinergics

35
Q

Which antipsychotic group is Clozapine (Clozaril) from?

A

Tricyclic antipsychotic

hasmultiple receptor activities: D2 antagonist, 5-HT2A antagonist, 5-HT1A partial agonist (helps cognitive symptoms

36
Q

Which antipsychotic group is Risperidone from?

A

Benzisoxazole

37
Q

Which antipsychotic group is Olanzapine (Zyprexa) from?

A

Tricyclic antipsychotic

hasmultiple receptor activities: D2 antagonist, 5-HT2A antagonist, 5-HT1A partial agonist (helps cognitive symptoms

38
Q

Which antipsychotic group is Sulpride (Meresa) from?

A

Benzamide

39
Q

Which antipsychotic group is Remoxipride (Roxiam) from?

A

Benzamide

40
Q

Which antipsychotic group is Ziprasidone (Geodon) from?

A

Benzisothiazole

41
Q

True or False - Aripiperazole (Abilify) can help positive symptoms, negative symptoms, and cognitive symptoms all while limiting EPS?

A

True - it acts as an antagonist in the limbic tissue (where DA is too high), partial agonist in the cortical tissue (where DA is low) and partial agonist in striatal tissue (which decreases EPS)

42
Q

True or False - Abilify is a potent D2 partial agonist and potent 5-HT2A antagonist?

A

True

43
Q

Which miscellaneous atypical antipsychotic has primarily 5-HT2A antagonism with almost no D2 antagonism and therefore no EPS?

A

Sertindole (Serdolect)

44
Q

Name (2) recently approved atypical antipsychotics?

A
  1. Asenapine

2. Iloperidone

45
Q

Name (3) cognitive symptoms of schizophrenia.

A
  1. impaired executive functioning
  2. memory impairment
  3. attention deficits

Medicinal Chemistry 3 (6 decks)

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