RX412: Chemistry of Benzodiazepines

What effects do all BZDs have?

Anti-anxiety

Sedation

Muscle relaxation (CNS Depression)

Seizure protection

Memory Impairment

Which BZD has the most anxiolytic effects?

Demoxopin

Which BZD has pronounced muscle relaxation?

Diazepam

What drug is this?

Diazepam

What is this drug given rectally to treat?

Seizures

What type of metabolization does this drug go through?

N-Demethylation

What is the t1/2 of this drug?

30-60 hours

What is this drug?

Desmethyldiazepam

What is the half-life of this drug?

30-100 hours

What is this drug a metabolite of?

Diazepam and chlordiazepoxide

Where do BZDs bind on the GABA receptor?

Between Alpha and Gamma subunits

Where does GABA bind on the GABA receptor?

Between alpha and beta subunits

How do BZDs work?

Increase activity of GABA by potentiating its binding. (GABA has inhibitory effects)

What can be substituted on R1?

H

Methyl

Carbonyl (Can be in ring structure) that can be de-alkylated (H on carbon alpha to nitrogen)

• Anything that can be hydroxylated (It can be a big chain as long as alpha carbon has an H)

What can be substituted on R7 to increase activity?

EWG

• Cl

• NO2

• CCl3

What things subbed on R7 would decrease activity?

EDG

• methyl

What type of interaction does the A ring have on the GABA receptor?

Pi-Pi

Is diazepam active as administered?

Yes, it also has an active metabolite

Where can this drug be metabolized and by what?

The chain on R1 by CYP3A4

CYP3A4 hydroxylates R3

What happens once R3 is metabolized in an OH?

Becomes glucoronated in the liver and is excreted

What type of solution does this drug need to be in to be soluble in water?

Acidic

Why can’t you give this drug in acidic solution?

Ring B opens and becomes inactive

What makes this drug need an acidic solution? (What gives it such a low pKa despite being a base?)

Imine (Bottom Nitrogen)

How is this drug formulated?

With cosolvents

• Propylene Glycol

• Polyethylene glycol

What is the DOA of short acting BZDs?

3-8 hours

What is the DOA of intermediate acting BDZs?

11-20 hours

What would adding a EWG on 2’ do to DOA?

Make the molecule short acting

What is this drug’s effects / what does it treat?

Memory problems

Anesthesia

Strong anxiolytic

Seizure

What is the nasal formulation of this drug used for?

Seizure

Why is this drug formulated with cosolvents?

It’s a nasal spray and needs acidic environments. That would hurt the nose.

What is this drug’s main route of metabolization?

Hydroxylation of the methyl via CYP3A4 and then gluconeration to be excreted.

How are BZDs containing triazolams formulated?

Oral because they aren’t basic so you can’t formulate them for injection

What level of potency does this drug have?

Highest of all BZDs?

What are the 3 BZDs with the highest affinity for GABA receptor?

Alprazolam

Lorazepam

Clonazepam

What is the main metabolization of this drug?

CYP3A4 hydroxylation of C3

What is this drug used for?

Rapid relief of anxiety

What is the main metabolization for this drug?

CYP3A4 mediated hydroxylation of C3

What level of DOA does this drug have?

Intermediate

What substitution on C3 will result in ultrashort half-life?

Esters

What is the level of DOA for this drug?

Ultra-short acting

What is the DOA of ultra-short acting BZDs?

45 minutes

What type of drug is this (Prodrug, softdrug, etc.)

Softdrug

What adjustments would need to be made for kidney failure / liver failure?

None

What substitution on C3 decreases activity?

OH

Why would you want an OH on C3?

Decrease DOA so no drug accumulation

Why is it beneficial for BZDs to be metabolized via conjugation instead of oxidative?

Oxidative metabolism gets worse as you age but not conjugative metabolism

What needs to be present for a drug to be short acting?

1-2 linked (Ring on nitrogen in B ring)

What effect does having CO2H substituted on R3 have?

Helped absorption and increase H2O solubility

What is the route of administration of this drug?

Oral

What type of drug is this?

BZD Prodrug

Why is this drug given orally?

Goes through beta keto acid decarboxylation in the acidity of the stomach

What would happen if you take this drug with orange juice?

Decrease conversion to active metabolite because increased acid in stomach decreases metabolism

What is this drug primarily used to treat?

Seizure

Would you expect this drug to be highly potent at GABA receptors?

Yes, it is a classic BZD

What is the main route of metabolization of this drug?

Reduction of the nitroxide into NH2

Is this drugs metabolite active?

No, NH2 is a EDG

What would a methyl group on R1 do to duration of action?

Increase because NH would still remain activity, so it would be an active metabolite.

What type of action does this drug have?

Antagonizes BZD receptor

What aspect of this molecule is crucial for its action?

Missing C ring

What is the DOA of this drug?

Ultra short

How is this drug given?

IV

What is this drug used for?

Reverse effects of BZD sedation post-operation

What are the adverse effects of this drug?

Seizures

What activity does this drug have?

5HT1A receptor partial agonist

What are the benefts of being a partial agonist of 5HT1A?

No sedation, no anticonvulsant activity, and no muscle relaxation.

How does this molecule elicit its antianxiety effects?

5HT1A partial agonist

What is the main metabolization route of this drug?

CYP3A4

What is this drug’s main metabolite? Is it active?

1-PP. ¼ as active as the parent

What is the effects of the a1 subtype of the GABA receptor being activated?

Leads to sedation of hypnotic effects

What are the adverse effects of a1 subunit activation?

Memory problems

What receptors do Z drugs act on?

BZ1 receptors (a1 subunit containing GABA receptors)

How do Z drugs act on BZ1 receptors?

Agonist

What is the primary concerning adverse effect of Z drugs (BZ1 agonist)?

Complex sleep behaviors

What is the main metabolization of this drug?

CYP3A4

Is this drug’s metabolite active?

No

What would be the effect of taking a CYP3A4 inducer with this drug?

Decrease activity through increased metabolization

What is the metabolic pathway of this drug?

Aldehyde oxidase and then that can go into CYP3A4 or UGT

What is the backbone of DORAs?

Core ring-like structure that locks in the conformation and then 2 groups that branch off of that

What type of drug is this?

Z drug

What are three ways this drug gets metabolized?

Esterase

CYP3A4 into 2 inactive drugs

What is this?

Melatonin

What are the effects of MT1 receptor activation?

Induces sleep

What are the effects of MT2 receptor activation?

Regulates circadian rhythm

What receptor does this drug act on?

MT1

What does this drug act on?

MT1 and MT2

What does this drug treat?

Non-24 hours sleep wake disorder for blind people who don’t get the light and dark queues

What type of drug is this?

Non-sedative hypnotic

What is the main metabolization route of this drug?

CYP1A2 (adds OH to omega-1 carbon)

What happens to this drug when you take it with Fluoxetine?

Increases activity by decreasing metabolization via CYP1A2

What type of drug is this?

TCA

What does this drug treat?

Sedative hypnotic for insomnia at low doses

What receptor does this drug act on?

H1 antagonist

What are DORAs?

Dual Orexin Receptor Antagonists

What are orexins?

excitatory neurotransmitter that promotes wakefulness

What are the effects of DORAs?

Decreases sleep latency

• Decrease time it takes to fall asleep

What type of sleep do DORAs increase?

REM and NREM

What receptor do DORAs act on?

Both OX-A and OX-B

What type of drug is this?

DORA

What does the left group do for this drug?

Increase potency due to less metabolization

What is this drugs biologic tendencies?

Very lipophilic / hydrophobic