Med Chem Quiz 9 (L33-35)

-sedative = drug that exerts calming effect

-hypnotic = drug that produces drowsiness and encourages onset and maintenance of sleep

-anxiolytic = drug that relieves excessive anxiety

Barbituates have a linear relationship when increasing dose with increased CNS depression (overdose more likely, benzodiazepines taper off)

Site of binding of barbituates not well defined

Many sedatives, hypnotics, and anti-anxiety drugs also have anti-epileptic activity

GABAa = post-synaptic inhibition

GABAb = pre-synaptic inhibition (slows release of neurotransmitters)

Both A and B produce CNS depression

Sedative and Hypnotic Agents Basic Overview

1. Two R’s at C-5-position needed for activity (replaces the 2 H's in barbituic acid)

2. ↑Number of C’s in C-5 R’s ⇒ ↑onset, ↓duration

-increase in lipophilicity (faster into CNS --> faster onset), but also permeates out of CNS quickly so metabolized quicker --> shorter duration

3. Polar groups, unsaturation, and branching on the C-5 R’s ⇒ ↑rate of metabolism, ↓duration

4. A methyl group @ N-1 position ⇒ ↑onset, ↓duration

5. Substitution on both nitrogens ⇒ loss of activity

6. Sulfur at the 2-position ⇒↑onset, ↓duration

-more lipophilic

Extra notes:

-barbituric acid has no CNS activity because its highly ionized

-tautomerizes to trihydroxy form

-NHs are acidic because they are between 2 carbonyls (so ionized)

-barbituates are enzymatic inducers

-continued use may lead to addiction

-primarily as anesthetics and anticonvulsants

SAR of barbituates

Ultra short acting (generally anasthetics) = less than 3 hours

Methohexital and Thiopental

Short acting (sedative hypnotic and preanesthetic) = 3-4 hours

Secobarbital and Pentobarbital

Intermediate Acting (sedative hypnotic) = 6-8 hours

Amobarbital and Butabarbital

Long Acting (anticonvulsant) = 10-16 hours

Phenobarbital

Barbituate Drugs

Secobarbital

-Used as hypnotic and preanesthetic

-C2

-Short-acting (duration = 3-4 hours)

-Onset = 10-15 min

-unsaturation and branching at 5 position lead to shorter duration (barbituate SAR)

Metabolism:

-alpha oxidation (allylic)

-epoxidation (can cause inactivation of CYPS) then hydrolysis

-omega-1 oxidation

Pentobarbital

-Used as hypnotic seddative and preanesthetic

-C2

-Short-acting (duration = 3-4 hours)

-Onset = 10-15 min

-unsaturation at 5 position leads to shorter duration (barbituate SAR)

Amobarbital

-intermediate-acting (duration = 6-8 hours)

-onset = 45-60 min

-C2

-sedative and hypnotic

Metabolism (hydroxylations):

-omega-1 oxidation or omega-oxidation

Butabarbital

-intermediate-acting (duration = 6-8 hours)

-onset = 45-60 min

-C3

-sedative and hypnotic

-just has one less carbon than amobarbital

Phenobarbital

-long-acting (Duration = 10-16 hours)

-onset = 30-60 min

-used as anti-convulsant (treatment of seizures)

Metabolism:

-oxidative hydroxylation at para position on phenyl ring

-glucuronidation of one NH (turns into chiral center --> preference of S metabolite over R)

Chloral Hydrate

-C4

-weakly acidic

-Reduced to an active metabolite or oxidized to inactive metabolite

-Drawbacks: bitter taste (take w/ fruit juice) and gastric irritation

-sedative and hypnotic, can suppress and prevent alcohol withdrawal symptoms

-can be synergistic w/ alcohol (leading to misuse)

Diphenhydramine

-OTC first generation antihistamine

-safe in children over 6

Zolpidem Tartrate (Ambien)

-known to be used in military for pilots to induce sleep

The 3-Z drugs:

-mimic benzodiazepines by selectively binding to type 1 BZ binding sites (associated with sleep and hypnotic effects)

-C4

-extensively metabolized after administration (very little eliminated unchanged)

-used for short term treatment of insomnia

Zaleplon (Sonata)

The 3-Z drugs:

-mimic benzodiazepines by selectively binding to type 1 BZ binding sites (associated with sleep and hypnotic effects)

-C4

-extensively metabolized after administration (very little eliminated unchanged)

-used for short term treatment of insomnia

Eszopiclone (Lunesta)

The 3-Z drugs:

-mimic benzodiazepines by selectively binding to type 1 BZ binding sites (associated with sleep and hypnotic effects)

-C4

-extensively metabolized after administration (very little eliminated unchanged)

-used for short term treatment of insomnia

Dexmedetomidine

-selective alpha-2 agonist (prevents release of NE and ATP to cause CNS depression)

-used as sedative in ICU for intubated or ventilated patients as infusion or injection; regional or general anesthetic

-also exists as film formulation for buccal or sublingual administration

-NOT controlled

-t1/2 = 2h (extensive metabolism)

Ramelteon (Rozerem)

-for insomnia (can be used for long term treatment)

-NOT controlled

-mimics melatonin, binding to MT1 and MT2 receptors

-sleeping aid without potential for abuse, no withdrawal symptoms

-t1/2 = 1-2.6 hours and F= >84% (longer and higher than melatonin)

-Problem: has first pass metabolism (only 1.8% reaching systemic cicrculation)

-DDI: fluoxamine (SSRI) is a strong CYP inhibitor --> AUC increase by 170 fold when used together (do NOT use rameleton and fluoxamine)

-major metabolite: hydroxylation --> has 1/10 activity but concentration can be 20-100x the parent drug (a lot of ramelteons effect from this)

Structure compared to melatonin

-methoxy in ring = conformational restriction

-replacing N with C = bioisosteric replacement

-ethyl group instead of methyl

Melatonin has poor and variable BA (F=10=56%), short t1/2 (20-60min)

MT1 --> sleep

MT2 --> circadian rhythm

Tasimelteon

-Preferentially binds to MT2 for circadian rhythm control

-not controlled

-t1/2=1-2 hours

-extensive metabolism

-cyclopropyl = conformational restriction

Indications:

1. Non-24 Hour Sleep Wake Disorder (N24HSWD) (usually a condition in totally blind people)

2. Night time sleep disturbance in Smith-Magneis Syndrome

Suvorexant

-t1/2 = 12h

-10 mg daily

All "rexants" properties:

-DORA = dual orexin receptor antagonists

-orexin is a neuropeptide hormone in CNS to control and keep people awake

-Antagonism of orexin OX1R and OX2R blocks the excitatory transmission of these receptors

-orexin A and B are excitatory neuropeptides that work on OX1R and OX2R

-OX1R (orexin A preferentially binds) and OX2R (orexin A and B binding)

-Taken 30 minutes before bedtime

-Used for treatment of insomnia (second line; first line is cognitive behavior therapy)

-food effect: food can delay onset (don't take with food or after meal)

-all C4

Lemborexant

-t 1/2 = 17-19h (longest of rexants)

-5 mg daily

All "rexants" properties:

-DORA = dual orexin receptor antagonists

-orexin is a neuropeptide hormone in CNS to control and keep people awake

-Antagonism of orexin OX1R and OX2R blocks the excitatory transmission of these receptors

-orexin A and B are excitatory neuropeptides that work on OX1R and OX2R

-OX1R (orexin A preferentially binds) and OX2R (orexin A and B binding)

-Taken 30 minutes before bedtime

-Used for treatment of insomnia (second line; first line is cognitive behavior therapy)

-food effect: food can delay onset (don't take with food or after meal)

-all C4

Daridorexant

-t1/2 = 8h

-25-50 mg daily

All "rexants" properties:

-DORA = dual orexin receptor antagonists

-orexin is a neuropeptide hormone in CNS to control and keep people awake

-Antagonism of orexin OX1R and OX2R blocks the excitatory transmission of these receptors

-orexin A and B are excitatory neuropeptides that work on OX1R and OX2R

-OX1R (orexin A preferentially binds) and OX2R (orexin A and B binding)

-Taken 30 minutes before bedtime

-Used for treatment of insomnia (second line; first line is cognitive behavior therapy)

-food effect: food can delay onset (don't take with food or after meal)

-all C4

Used as anxiolytics, sedative-hypnotics, anesthetics, skeletal-muscle relaxants, and antiepileptic drugs

In general do not promote the metabolism of other drugs (unlike barbiturates)

All benzodiazepines have muscle relaxant properties and all are C4

SAR:

1. An electron-withdrawing group @ 7-position (or 8 in triazolo) required for activity. Stronger withdrawing groups result in better activity. X is usually a Cl or NO2.

2. A phenyl @ position 5 needed for good activity.

o Electron-withdrawing Y (Cl or F) at o-position or both o-positions ⇒ ↑activity.

o A substituent at the p-position ⇒ ↓activity

o hydroxylation unlikely if EWG on phenyl

3. Saturation of 4,5-double bond (imine) ⇒ ↓activity

4. A hydroxyl @ 3-position is tolerated

5. A carbonyl at 2-position optimal for activity

6. Small R @ 1-nitrogen for maximal activity

o If too large --> prodrug (needs to be removed for activation)

Benzodiazepine SAR

Chlordiazepoxide Hydrochloride

-anxiolytic, sedative

Metabolism:

-demetyhlation

-alpha-hydroxylation (at 3 position) --> active metabolite

-anoxide can be reduced to imine (Active)

-hydroxylation on phenyl

Diazepam (Valium)

-for relief of anxiety and systematic relief of acute alcohol withdrawal as a skeletal muscle relaxant; can be used for the treatment of seizures

-Relieves skeletal muscle spasms, tetanus, spasticity caused by cerebral palsy and paraplegia

-prolonged use may lead to dependence

-t1/2 = 60-72 hr

-nordiazepam (demethylated active metabolite) t1/2 can be as long as 200h

Metabolized to temazepam (which is an active drug itself)

-alpha-hydroxylation at 3 position

-temazepam is used clinically as hypnotic agent

-t1/2 = 4-18h

Temazepam is metabolized to oxazepam (which is an active drug itself)

-demethylation

-t1/2 = 6-8h

-used clinically treatment of anxiety and alcohol withdrawal symptoms

-can be used in elderly patients w/ liver dysfunction because there is no further metabolism that occurs

Clorazepate Dipotassium

-prodrug for nordiazepam due to COOH at 3 position (needs to be removed by decarboxylation to get activated)

-used for anxiety, treatment of alcohol withdrawal symptoms, and epilepsy

-nordiazepam half life = 36-200h

Flurazepam

-prodrug (bulky R group at 1 position - removed metabolically through oxidative dealyklation)

-N-desalkyl major active metabolite --> t1/2 = 47-100h, good sedative and hypnotic activity (can help normal REM cycles for sleep)

-used for sleep inducing activity

-Same structure as nordiazepam with additional Fluorine (EWG) on phenyl (provides metabolic resistance to hydroxylation)

Quazepam

-Sulfur at 2 position (more lipophilic)

-for patients with insomnia

-N-desalkyl metabolite (t1/2 = 47-100h) (same metabolism as flurazepam but its not a prodrug because parent drug is active --> CF3 is small enough R group)

Lorazepam

-Used to treat anxiety and as anticonvulsant

-treatment of choice for delirium tremors (DTs), which is a severe form of alcohol withdrawal syndromes

-Cl on both phenyls (prevent hydroxylation)

Alprazolam

-Triazolobenzodiazepine

-CH3 on triazolo ring (more lipophilicity), no second Cl on phenyl

-0.25-0.5 mg TID

-for panic disorder and anxiety

-also for agorophobia, which is fear of public spaces

Triazolobenzodiazepine potency: Triazolam > Alprazolam > Estazolam

Estazolam

-Triazolobenzodiazepine

-No CH3 on triazolo ring (more lipophilicity) and no second Cl on phenyl

-1-2mg at bedtime

-for insomnia

Triazolobenzodiazepine potency: Triazolam > Alprazolam > Estazolam

Triazolam

-Triazolobenzodiazepine

-CH3 on triazolo ring (more lipophilicity) AND second Cl on phenyl

-0.25 mg at bedtime for insomnia

-known to be associated with greater frequency of side effects (rebound anxiety, amnesia) because most potent

-withdrawn in other countries but still used in U.S. w/ low doses

Triazolobenzodiazepine potency: Triazolam > Alprazolam > Estazolam

Flumazenil

-Benzodiazepine receptor antagonist

-Soft drug

-ester group allows for ester hydrolysis

-will bind to receptor without CNS depressive effects to prevent benzodiazepines in patients system from activating GABAa receptors

-usually given IV (need to be administered quickly) --> 200 mcg over 1-2 min until effects in patient (max dose is 3 mg/hr)

-very short t1/2 --> 7-15 min in brain, 20-30 min systemic, 40-80 min terminal

-sometimes if you stop giving it, patients may fall back into CNS depression (so may have to readminister)

-No phenyl ring at 5 position which is required for activation of receptor

-side effects: associated with occurence of seizures

Buspirone (Buspar)

-5HT1A receptor agonist

-partial agonist at PRE-synaptic 5HT1A

-full agonist at POST-synaptic 5HT1A

-used for anxiety (no anticonvulsant or muscle relaxant properties)

-NOT controlled (no sedative effects, no dependence or withdrawal)

-moderate D2 affinity

-after cleavage, 1-PP potent alpha-2-antagonist (promotes release of NE)

-t1/2 = 2-3h

Gepirone

-same structure as buspirone but removed 2C on end ring

-approved for MDD

-5HT1A partial agonist

-No D2 affinity

-not controlled

-produces 1-PP metabolite (strong alpha-2 antagonism promoting release of NE)

-Exxua = ER formulation for QD dosing

-t1/2 = 5h

Hydroxyzine

-first generation antihistamine (H1 antagonist)

-not controlled

-used as mild tranquilizer to reduce anxiety

-side effect: teratogenic activity

Meprobamate

-Miltown brand name

-omega-1 oxidation

-used to control anxiety

-"happy pill"

-mechanism not known

-can lead to physical dependence (C4)

Methocarbomal (Robaxin)

-skeletal muscle relaxant

-used to relieve discomfort associated with acute and painful musculoskeletal conditions; can also be used to control neuromuscular aspects of tetanus

-carbamate of guafenesin (an expectorant)

Often used in combo with analgesics

-with acetominophen --> Robexacet

-with ibuprofen --> Robax Platinum

-with aspirin --> Robaxisal

Carisoprodol

-skeletal muscle relaxant

-similar to meprobamate structure (metabolically turns into meprobamate

-CNS depression, abuse potential (C4)

-Works directly on spinal cord area, not directly on skeletal muscle cells

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