Lesson 4.2. CNS Depressants

Anxiety Disorders

group mental illness described as having significant levels of anxiety and fear that interfere with social and occupational functioning, but should not be associated to an exogenous factor or medical condition

Generalized anxiety disorder

Example of Anxiety disorders:

a. chronic abnormally high levels of anxiety

b. other examples

a = ?

Phobias, Social phobia, OCD, and PTSD

Example of Anxiety disorders:

a. chronic abnormally high levels of anxiety

b. other examples

b = ?

genetic

Anxiety disorder are not a._________ nor caused by b.____________, mostly it is associated with c.______________________.

a = ?

neural damage

Anxiety disorder are not a._________ nor caused by b.____________, mostly it is associated with c.______________________.

b = ?

GABA transmission

Anxiety disorder are not a._________ nor caused by b.____________, mostly it is associated with c.______________________.

c = ?

Gamma aminobutyric acid

meaning of GABA

GABA

major inhibitory neurotransmitter in the Central Nervous System (GABA A and GABA B)

heteropentameric

GABA Receptors is ______________ in structure that provides binding sites to different drug molecules.

Benzodiazepines and Non-Benzodiazepines GABA Agonist

Anxiolytic Drugs

Benzodiazepine ring allosteric site

Benzodiazepines Mechanism of Action:

a. Benzodiazepine binds to the ___________________ to modulate Cl- conduction.

b. Benzodiazepine increases the binding rate of GABA to __________________.

c. Cl- hyperpolarizes the membrane, decreasing __________________.

a = ?

GABA A receptors

Benzodiazepines Mechanism of Action:

a. Benzodiazepine binds to the ___________________ to modulate Cl- conduction.

b. Benzodiazepine increases the binding rate of GABA to __________________.

c. Cl- hyperpolarizes the membrane, decreasing __________________.

b = ?

membrane firing

Benzodiazepines Mechanism of Action:

a. Benzodiazepine binds to the ___________________ to modulate Cl- conduction.

b. Benzodiazepine increases the binding rate of GABA to __________________.

c. Cl- hyperpolarizes the membrane, decreasing __________________.

c = ?

Flumazenil

Treatment for overdose of Benzodiazepines which is a competitive molecule for Benzod

CYP 3A4 and 2C19

Metabolism of Benzodiazepines (BZDs)

a. Phase 1 metabolism

b. diazepam and flurazepam

c. N-desmethyldiazepam, C1methyl, C4methylene of Class B BZDs

a = ?

N-dealkylation

Metabolism of Benzodiazepines (BZDs)

a. Phase 1 metabolism

b. diazepam and flurazepam

c. N-desmethyldiazepam, C1methyl, C4methylene of Class B BZDs

b = ?

C3 aliphatic hydroxylation

Metabolism of Benzodiazepines (BZDs)

a. Phase 1 metabolism

b. diazepam and flurazepam

c. N-desmethyldiazepam, C1methyl, C4methylene of Class B BZDs

c = ?

Benzodiazepine Pharmacophore

Ring A

Benzodiazepine Structure-Activity Relationship

• aromatic ring essential for binding and activity

electronegative group (Cl, F, Br)

Benzodiazepine Structure-Activity Relationship

Ring A

• At C7, the presence of _________________________, increases drug activity

C6, C8, C9 substitution

Benzodiazepine Structure-Activity Relationship

Ring A

• _______________________ significantly decreases drug activity

Ring B

Benzodiazepine Structure-Activity Relationship

• 7 sided ring

small alkyl (Hydrogen and methyl) group at N1

Benzodiazepine Structure-Activity Relationship

Ring B

• promotes receptor affinity and activity

proton-accepting group (O/S)

Benzodiazepine Structure-Activity Relationship

Ring B

• At C2, the presence of _______________________ is required for ligand binding

-OH

Benzodiazepine Structure-Activity Relationship

Ring B

• At C3, _______ (hydrophilic) promotes faster excretion = short DOA

Ring C

Benzodiazepine Structure-Activity Relationship

• C5-phenyl ring not required for activity

receptor binding

Benzodiazepine Structure-Activity Relationship

• Ring C promotes hydrophobic and steric interaction for __________________

increases

Benzodiazepine Structure-Activity Relationship

Ring C

• The presence of electron-attracting groups at ortho (C2’ or C6’) and diortho position (C2’ and C6’) _________ activity

decreases

Benzodiazepine Structure-Activity Relationship

Ring C

• The presence of substitutions at para position (C1’ or C4’) __________ activity

Electron-rich ring (s-triazole/imidazole)

Benzodiazepine Structure-Activity Relationship

Annelation

• ____________________at C1-C2 of Ring B increases Benzodiazepine affinity

-epam/-epates

suffix for Class A Benzodiazepine

-olam

suffix for Class B Benzodiazepine

Class A and B

Structure-Activity Relationship of Benzodiazepine:

a. Ring A, B, C are applicable for ______________

b. Annelation is applicable for ____________

a = ?

Class B

Structure-Activity Relationship of Benzodiazepine:

a. Ring A, B, C are applicable for ______________

b. Annelation is applicable for ____________

b = ?

Structure of Diazepam

Diazepam

Examples of Benzodiazepines Anxiolytics:

• prototype Class A drug

• long-acting

• has the greatest affinity

Structure of Lorazepam

Lorazepam

Examples of Benzodiazepines Anxiolytics:

• prototype Class A drug

• presence of C3-OH

• short-acting

Structure of Alprazolam

Alprazolam

Examples of Benzodiazepines Anxiolytics:

• prototype Class B drug

• contains a triazole ring

Structure of Midazolam

Midazolam

Examples of Benzodiazepines Anxiolytics:

• prototype Class B drug

• contains an imidazole ring

Non-BZD GABA Agonist

drugs that do not possess the BZD pharmacophore but exhibits anxiolytic and sedative/hypnotic activity thru other mechanism

zolpidem, eszopiclone, zaleplon

Non-BZD GABA Agonist Drugs

highly selective for alpha-GABA A receptor subtype

Mechanism of Action for Non-BZD GABA Agonist

Insomnia

Use of Non-BZD GABA Agonist

CYP 3A4, 1A2 and 2D6

Metabolism of Non-BZD GABA Agonist:

a. Phase 1 metabolism

b. Happens in zaleplon

a = ?

first-pass effect

Metabolism of Non-BZD GABA Agonist:

a. Phase 1 metabolism

b. Happens in zaleplon

b = ?

Structure of Zolpidem

Zolpidem

Non-BZD GABA Agonist

• prototype non-BZD

• with an imidazopyridine ring

• has 3 areas are essential for binding

R1

Zolpidem

• electron-rich planar aromatic region

R2

Zolpidem

• free rotating aromatic ring region

R3

Zolpidem

• antiplanar region

electronegative group substitution

Structure-Activity Relationship of Non-BZD GABA Agonist (Zolpidem)

• In R1/R3, _____________________ decreases activity.

Bulky N-substitution

Structure-Activity Relationship of Non-BZD GABA Agonist (Zolpidem)

• In R3, _____________________ decreases activity.

Structure of Eszopiclone

Eszopiclone

Non-BZD GABA Agonist

• with cyclopyrrolone ring

• binds at allosteric site of GABA A receptors

Structure of Zaleplon

Zaleplon

Non-BZD GABA Agonist

• with pyrazolopyrimidine ring

• -CN group provides receptor selectivity

Sedative/Hypnotics

• drugs which depress or slow down the body’s function

• its activity can range from calming to sleep promotion

Ascending Reticular Activating System (ARAS)

Arousal input in the body regulated by Glutamate

Tuberomammalian nucleus (TBN) and Suprachiasmatic nucleus (SCN)

facilitate wakefulness via different mechanisms

GABA A receptor

Sedative/ Hypnotics work primarily as:

a. ____________ agonist

b. __________________ system modulator

a = ?

histamine/melatonin

Sedative/ Hypnotics work primarily as:

a. ____________ agonist

b. __________________ system modulator

b = ?

Sedative/Hypnotics Drugs

BZDs, non-BZD GABAA agonist, barbiturates, melatonin receptor agonist, H1-receptor agonist

Barbiturates

agents of choice as sedative/hypnotic until they developed tolerance, dependence and/or toxicity

ultra-short acting

Barbiturates can be:

a. less than 3 hours

b. 3-4 hours

c. 6-8 hours

d. 10-16 hours

a = ?

short-acting

Barbiturates can be:

a. less than 3 hours

b. 3-4 hours

c. 6-8 hours

d. 10-16 hours

b = ?

intermediate-acting

Barbiturates can be:

a. less than 3 hours

b. 3-4 hours

c. 6-8 hours

d. 10-16 hours

c = ?

long-acting

Barbiturates can be:

a. less than 3 hours

b. 3-4 hours

c. 6-8 hours

d. 10-16 hours

d = ?

sulfur

A barbiturates is ultra-short acting and is considered as an anesthetics which is characterized by the presence of:

alternating ketone (3) and nitrogen (2)

Structurally, barbiturates are characterized by:

binds to GABA A receptor

Mechanism of Action of Barbiturates:

a. __________________________ = increasing GABA binding

b. increased GABA binding increases _________________= reversible inhibition of excitatory neurons.

a = ?

Cl- ion transport

Mechanism of Action of Barbiturates:

a. __________________________ = increasing GABA binding

b. increased GABA binding increases _________________= reversible inhibition of excitatory neurons.

b = ?

liver metabolism

Metabolism of Sedative/Hypnotics:

a. significant ___________________

b. C5-substituent ____________

c. other metabolism

a = ?

oxidation

Metabolism of Sedative/Hypnotics:

a. significant ___________________

b. C5-substituent ____________

c. other metabolism

b = ?

glucuronidation and sulfation

Metabolism of Sedative/Hypnotics:

a. significant ___________________

b. C5-substituent ____________

c. other metabolism

c = ?

Barbituric Acid

Barbiturate pharmacophore

structure of Barbiturate pharmacophore

Acidic N and C5-H

Structure Activity Relationship:

Barbiturates

• _____________________ results into inactivity

C5 substitution (except H)

Structure Activity Relationship:

Barbiturates

• _____________ results to maximal activity

N1 and N3 alkyl substitution

Structure Activity Relationship:

Barbiturates

• _______________ increases lipophilicity

anesthetics

Structure Activity Relationship:

Barbiturates

• The replacement of =O with =S produces thiobarbiturates, ultra-short-acting agents,  which is used for __________________.

ethyl and phenyl

Structure Activity Relationship:

Barbiturates (C5 di-substitution)

a. it is long acting when the di-substitutions of C5 are:

b. it is intermediate acting when the di-substitutions of C5 are:

c. it is short acting when the di-substitutions of C5 are:

a = ?

ethyl or phenyl

Structure Activity Relationship:

Barbiturates (C5 di-substitution)

a. it is long acting when the di-substitutions of C5 are:

b. it is intermediate acting when the di-substitutions of C5 are:

c. it is short acting when the di-substitutions of C5 are:

b = ?

neither ethyl or phenyl

Structure Activity Relationship:

Barbiturates (C5 di-substitution)

a. it is long acting when the di-substitutions of C5 are:

b. it is intermediate acting when the di-substitutions of C5 are:

c. it is short acting when the di-substitutions of C5 are:

c = ?

branched

Structure-Activity Relationship

The following shortens Barbiturates’ duration of action when:

a. presence of __________ chains

b. presence of _____________ side chains

c. side chain is larger than the _________________

a = ?

unsaturated

Structure-Activity Relationship

The following shortens Barbiturates’ duration of action when:

a. presence of __________ chains

b. presence of _____________ side chains

c. side chain is larger than the _________________

b = ?

ethyl group

Structure-Activity Relationship

The following shortens Barbiturates’ duration of action when:

a. presence of __________ chains

b. presence of _____________ side chains

c. side chain is larger than the _________________

c = ?

Structure of Phenobarbital

Phenobarbital

Examples of Barbiturates

• long-acting agent due to the presence of ethyl and phenyl at C5

Structure of Butabarbital

Butabarbital

Examples of Barbiturates

• intermediate-acting agent due to the presence of ethyl at C5

Structure of Secobarbital

Secobarbital

Examples of Barbiturates:

• short-acting agents due to the presence of double bonds and branching

Structure of Thiopental

Thiopental

Examples of Barbiturates:

• ultra short-acting agent used as an anesthetic due to the substitution of =S from =O

Melatonin Receptor Agonists

drugs which promotes sleep by binding into melatonin receptors in the brain (MT1R and MT2R)

Suprachiasmatic nucleus (SCN)

Mechanism of Action of Melatonin Receptor Agonists:

a. binds to MT1R decreasing ________________________ firing promoting sleep

b. binds to MT2R affecting __________________ (CNS clock)

a = ?

circadian rhythm

Mechanism of Action of Melatonin Receptor Agonists:

a. binds to MT1R decreasing ________________________ firing promoting sleep

b. binds to MT2R affecting __________________ (CNS clock)

b = ?