Medicinal Chem: Sedative hypnotics and narcolepsy
The ideal sedative/hypnotic will do what?
- Cause transient decrease in level of consciousness for sleep w/o lingering effects
- Have no potential for decreasing/arresting respiration
- Produce no abuse, addiction, tolerance, or dependence
How do barbiturates affect glutaminergic and GABAergic transmission?
- Depress glutaminergic
- Enhance GABAergic
Which subunit is the most widely expressed on the GABAa receptor and what does it modulate?
Alpha1; modulates sleep
What are alpha 4, 5, and 6 responsible for on the GABA receptor?
- Anxiolytic activity
- muscle relaxant
- Cognitive fxn
Barbs are antagonists of which glutamate receptors?
Barbs SAR for good hypnotic activity
- Must be weak organic acids
- Have 5,5-di- substituted groups - LIPOPHILIC
What does acidity of a barb result from?
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
Barbs all have which group?
What are the possible 5b groups barbs can have?
- Pheno- (phenyl)
- Buta- (1-methylpropyl)
- Pento- (1-methylbutyl)
- Amo- (3-methylbutyl)
What drives the faster onset of barbs (and the shorter duration)?
Which 5b group on barbs is the least lipophilic?
Which 5b group on barbs is the most lipophilic?
T/F: More lipophilic barb = faster onset = slower into brain = quicker redistributed out of brain
Where do BZDs bind?
b/w α and γ subunits
Secobarbital is a derivative of ____________ w/ a 5a-propene
Secobarbital brand name
Why should barbs not be used long term as hypnotics?
Lots of SE, including:
- REM rebound
- CNS confusion/agitation/irritability
List two short acting barbs
List the long acting barb
List the two intermediate acting barb
Thibarbituates have a ___________(greater/lesser) lipophilicity compared to respective oxy-derivatives.
T/F: Thibarbituates lead to greater potency, faster time of onset, but longer duration of action.
Thibarbituates are not as useful for insomnia, but are excellent for ______________
What position is preferred for barb metabolism on the phenyl ring?
What are the steps of barb metabolism?
- Phase I -- Oxidation
- Phase II -- Conjugation
What effects do BZDs have on sleep?
- Increast total sleep
- Decrease nocturnal wakefulness
- Decrease bodymvmts
- Decrease awakenings
- Decrease time of onset of sleep
BZDs act __________ to enhance GABA binding
BZ1 receptors = ______% of receptors
BZ2 receptors = ______% of receptors
BZDs Ring A SAR
- Must be aromatic : pi-pi stack w/ aromatic AA in GABAa-R
- Electronegative groups (halogen, N) at 7-position = increase binding and anxiolytic / hypnotic activity
BZDs Ring B SAR
- A proton accepting group (C=O, C=S, C=N) required; interacts w/ AA in receptor that is proton donor via H-bond
- Accepting group needs to be co-planar w/ ring A
- 3-Hydroxy groups have strong activity and are excreted faster
- N1-alkyl side chains add lipophilicity and increase BBB
- Annealing of 4th ring = higher affinity
BZDs Ring C SAR
- Required for agonisms in vivo
- May contribute to electronic interactions w/ receptor
- Ortho subs (C11) retain activity, increase lipophilicity and BBB crossing (May contribute to anti-planarity w/ ring AB system)
- p-subs inactive (C13)
Duration of BZDs is limited by their________
Which BZDs have long acting, active metabolites?
T/F: Flumazenil is a pure agonist, blocking access to the BZD site, but not inducing any Cl- conductivity.
T/F: Flumazenil is used for Barb OD.
Which BZD is shortest acting?
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)
How can we change the structure of a BZD in order to decrease hangover effects?
Annealing of 4th group
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
How are non-BZD agonists metabolized?
CYP450-3A (eszopiclone also met. by CYP1A2)
- α1 subunit selective
- Greatest potency of Z drugs
- p-CH3 groups on FRAR and PAR responsible for α1 selectivity
- Removal of imidazole N of ERR = loss of selectivity
- AP region responsible for binding affinity and selectivity (steric bulk decreases both)
What are the routes of metabolism for Zolpidem?
- CYP3A4 (major)
How would the effects of Zolpidem be affected if taken w/ alcohol?
Competes w/ alcohol for binding site = increased effects of both
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.
Zolpidem should be taken on a(n) __________ (full/empty) stomach
What is a consideration for Zolpidem in the elderly or those with hepatic dysfunction?
Reduce the dose bc of decreased CYP3A4 activity
T/F: Testosterone increases CYP3A4 activity.
What is Eszopiclone metabolized by?
T/F: Eszopiclone shows high binding affinity for α1 and α2 and its binding site overlaps the BZD site.
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
What enzyme metabolizes caffeine?
Which Z drug has the most rapid onset and shortest half-life (t1/2 = 1hr)?
Zaleplon brand name
T/F: Ramelteon has no anxiolytic, anticholinergic, amnesic, or CNS depressant effects
T/F: Zaleplon has a high affinity for α1 subunits, some affinity for α5 subnunits, and tends to accumulate in fatty tissues.
Zaleplon has weak SAR, but the _____ group seems to be important for selectivity
Zaleplon has a __________ (strong/weak) first pass effect
Strong -- 30% oral bioavailability
Eszopiclone brand name
- 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 is rapidly transformed into what?
Trichloroethanol (prolonged active metabolite)
T/F: Chloral hydrate exerts barb-like effects on the GABAa receptor.
What drug inhibits aldehyde dehydrogenase?
Where in the hypothalamus are histamine (H1) receptors highly localized?
- Tuberomammillary nucleus
- suprachiasmatic nucleus
A larger log P of barbs is associated w/ a __________(longer/shorter) onset time and a __________(longer/shorter) duration.
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.
List some drugs that display anti-histaminergic and anti-cholinergic activity
- Diphenhydramine (benadryl)
- Triprolidine (Actifed)
- Doxylamine (Unisom)
What is known as the "natural master clock keeper?"
Melatonin activates what GPCRs and where?
MT1 and MT2; Suprachiasmatic nucleus
Antagonists of MT1 and MT2 will theoretically induce alertness. Why is this important?
For shift workers
What is an example of an MT receptor agonist?
Ramelteon brand name
T/F: Ramelteon has no affinity for GABA or other NT receptors.
What physiological factors contribute to the conversion of serotonin to melatonin?
- Drop in body temp
What is Ramelteon metabolized by?
Does Ramelteon cause physical/psychological dependence?
T/F: Ramelteon is a controlled drug
Suvorexant brand name
What is the first drug in the DORA class?
Suvorexant is highly ____________ (lipophilic/hydrophilic)
What metabolizes Suvorexant?
- CYP 3A4 (major)