Medicinal Chem: Sedative hypnotics and narcolepsy

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1

The ideal sedative/hypnotic will do what?

  1. Cause transient decrease in level of consciousness for sleep w/o lingering effects
  2. Have no potential for decreasing/arresting respiration
  3. Produce no abuse, addiction, tolerance, or dependence
2

How do barbiturates affect glutaminergic and GABAergic transmission?

  • Depress glutaminergic
  • Enhance GABAergic
3

Which subunit is the most widely expressed on the GABAa receptor and what does it modulate?

Alpha1; modulates sleep

4

What are alpha 4, 5, and 6 responsible for on the GABA receptor?

  • Anxiolytic activity
  • anticonvulsant
  • muscle relaxant
  • Cognitive fxn
5

Barbs are antagonists of which glutamate receptors?

AMPA

6

Barbs SAR for good hypnotic activity

  • Must be weak organic acids
  • Have 5,5-di- substituted groups - LIPOPHILIC
7

What does acidity of a barb result from?

ene-ol tautomerization

8

Describe ene-ol tautomerization

  • The 2 position carbonyl takes on an acidic character due to tautomerization
  • Position favored due to location b/w 2 electronegative N
  • Favored structure contributes to binding at physiological pH
9

Barbs all have which group?

5a-ethyl

10

What are the possible 5b groups barbs can have?

  • Pheno- (phenyl)
  • Buta- (1-methylpropyl)
  • Pento- (1-methylbutyl)
  • Amo- (3-methylbutyl)
11

What drives the faster onset of barbs (and the shorter duration)?

Lipophilicity

12

Which 5b group on barbs is the least lipophilic?

Phenobarb

13

Which 5b group on barbs is the most lipophilic?

Pentobarb

14

T/F: More lipophilic barb = faster onset = slower into brain = quicker redistributed out of brain

False

15

Where do BZDs bind?

b/w α and γ subunits

16

Secobarbital is a derivative of ____________ w/ a 5a-propene

Pentobarbital

17

Secobarbital brand name

Seconal

18

Why should barbs not be used long term as hypnotics?

Lots of SE, including:

  • addiction
  • REM rebound
  • anxiety
  • CNS confusion/agitation/irritability
19

List two short acting barbs

  • Pentobarb
  • Secobarb
20

List the long acting barb

Phenobarb

21

List the two intermediate acting barb

  • Amobarb
  • Butabarb
22

Thibarbituates have a ___________(greater/lesser) lipophilicity compared to respective oxy-derivatives.

Greater

23

T/F: Thibarbituates lead to greater potency, faster time of onset, but longer duration of action.

False

24

Thibarbituates are not as useful for insomnia, but are excellent for ______________

Anesthetic

25

What position is preferred for barb metabolism on the phenyl ring?

Open para

26

What are the steps of barb metabolism?

  1. Phase I -- Oxidation
  2. Phase II -- Conjugation
27

What effects do BZDs have on sleep?

  • Increast total sleep
  • Decrease nocturnal wakefulness
  • Decrease bodymvmts
  • Decrease awakenings
  • Decrease time of onset of sleep
28

BZDs act __________ to enhance GABA binding

Allosterically

29

BZ1 receptors = ______% of receptors

60-70%

30

BZ2 receptors = ______% of receptors

20-30%

31

BZDs Ring A SAR

  1. Must be aromatic : pi-pi stack w/ aromatic AA in GABAa-R
  2. Electronegative groups (halogen, N) at 7-position = increase binding and anxiolytic / hypnotic activity
32

BZDs Ring B SAR

  1. A proton accepting group (C=O, C=S, C=N) required; interacts w/ AA in receptor that is proton donor via H-bond
  2. Accepting group needs to be co-planar w/ ring A
  3. 3-Hydroxy groups have strong activity and are excreted faster
  4. N1-alkyl side chains add lipophilicity and increase BBB
  5. Annealing of 4th ring = higher affinity
33

BZDs Ring C SAR

  1. Required for agonisms in vivo
  2. May contribute to electronic interactions w/ receptor
  3. Ortho subs (C11) retain activity, increase lipophilicity and BBB crossing (May contribute to anti-planarity w/ ring AB system)
  4. p-subs inactive (C13)
34

Duration of BZDs is limited by their________

Metabolism

35

Which BZDs have long acting, active metabolites?

  • Flurazepam
  • Quazepam
36

T/F: Flumazenil is a pure agonist, blocking access to the BZD site, but not inducing any Cl- conductivity.

False

37

T/F: Flumazenil is used for Barb OD.

False

38

Which BZD is shortest acting?

Temazepam

39

What BZD has sedative effects that are 7-10x as potent as other BZDs and causes anterograde amnesia? (used as a date rape drug and is no longer on market)

Flunitrazepam

40

How can we change the structure of a BZD in order to decrease hangover effects?

Annealing of 4th group

41

Describe the characteristics of non-BZDs agonists of the GABAa receptor BZD binding site

  • Strictly hypnotic activity
  • Short t1/2
  • Decreased ability to cause dependence
42

How are non-BZD agonists metabolized?

CYP450-3A (eszopiclone also met. by CYP1A2)

43

Zolpidem SAR

  1. α1 subunit selective
  2. Greatest potency of Z drugs
  3. p-CH3 groups on FRAR and PAR responsible for α1 selectivity
  4. Removal of imidazole N of ERR = loss of selectivity
  5. AP region responsible for binding affinity and selectivity (steric bulk decreases both)
44

What are the routes of metabolism for Zolpidem?

  • CYP3A4 (major)
  • CYP1A2
  • CYP2D6
45

How would the effects of Zolpidem be affected if taken w/ alcohol?

Competes w/ alcohol for binding site = increased effects of both

46

T/F: Men metabolize Zaleplon faster than women, so men generally take a dose of 10 mg at bedtime, while women take 5 mg at bedtime.

False

47

Zolpidem should be taken on a(n) __________ (full/empty) stomach

Empty

48

What is a consideration for Zolpidem in the elderly or those with hepatic dysfunction?

Reduce the dose bc of decreased CYP3A4 activity

49

T/F: Testosterone increases CYP3A4 activity.

True

50

What is Eszopiclone metabolized by?

  • CYP3A4
  • CYP1A2
51

T/F: Eszopiclone shows high binding affinity for α1 and α2 and its binding site overlaps the BZD site.

False

52

T/F: In contrast to racemate, the S-enantiomer of Eszopiclone is devoid of substantial residual sedative/cogniitive effects and has a 50 fold greater affinity than R

True

53

What enzyme metabolizes caffeine?

CYP1A2

54

Which Z drug has the most rapid onset and shortest half-life (t1/2 = 1hr)?

Zaleplon (Sonata)

55

Zaleplon brand name

Sonata

56

T/F: Ramelteon has no anxiolytic, anticholinergic, amnesic, or CNS depressant effects

True

57

T/F: Zaleplon has a high affinity for α1 subunits, some affinity for α5 subnunits, and tends to accumulate in fatty tissues.

False

58

Zaleplon has weak SAR, but the _____ group seems to be important for selectivity

CN

59

Zaleplon has a __________ (strong/weak) first pass effect

Strong -- 30% oral bioavailability

60

Eszopiclone brand name

Lunesta

61
  • Widely used in 50s and 60s, now primarily used in peds
  • Rapid sleep onset (<1 hr) and good duration (4-8)
  • Devoid of respiratory affects, no analgesic/anxiolytic affects

Chloral Hydrate

62

Chloral hydrate is rapidly transformed into what?

Trichloroethanol (prolonged active metabolite)

63

T/F: Chloral hydrate exerts barb-like effects on the GABAa receptor.

True

64

What drug inhibits aldehyde dehydrogenase?

Disulfuram

65

Where in the hypothalamus are histamine (H1) receptors highly localized?

  • Tuberomammillary nucleus
  • suprachiasmatic nucleus
66

A larger log P of barbs is associated w/ a __________(longer/shorter) onset time and a __________(longer/shorter) duration.

Shorter, shorter

67

T/F: Drugs that do not get into the brain will not have an effect on histamine H1 receptors that would cause sleep if inhibited.

True

68

List some drugs that display anti-histaminergic and anti-cholinergic activity

  • Diphenhydramine (benadryl)
  • Triprolidine (Actifed)
  • Doxylamine (Unisom)
69

What is known as the "natural master clock keeper?"

Melatonin

70

Melatonin activates what GPCRs and where?

MT1 and MT2; Suprachiasmatic nucleus

71

Antagonists of MT1 and MT2 will theoretically induce alertness. Why is this important?

For shift workers

72

What is an example of an MT receptor agonist?

Ramelteon (Rozerem)

73

Ramelteon brand name

Rozerem

74

T/F: Ramelteon has no affinity for GABA or other NT receptors.

True

75

What physiological factors contribute to the conversion of serotonin to melatonin?

  • Calcium
  • Drop in body temp
76

What is Ramelteon metabolized by?

  • CYP1A2
  • CYP3A4
  • CYP2C
77

Does Ramelteon cause physical/psychological dependence?

No

78

T/F: Ramelteon is a controlled drug

False

79

Suvorexant brand name

Belsomra

80

What is the first drug in the DORA class?

Suvorexant

81

Suvorexant is highly ____________ (lipophilic/hydrophilic)

Lipophilic

82

What metabolizes Suvorexant?

  • CYP 3A4 (major)
  • CYP2C19