Lesson 4.5. CNS Stimulants

Methylxanthines

xanthine derivatives found in plants that acts as CNS Stimulants

phosphodiesterase

Mechanism of Action of Methylxanthines:

a. competitive inhibition of ______________________

b. antagonism of ______________________

a = ?

adenosine receptors

Mechanism of Action of Methylxanthines:

a. competitive inhibition of ______________________

b. antagonism of ______________________

b = ?

Caffeine, Theophylline, Theobromine

Potency of Methylxanthine in CNS Stimulation

Caffeine, Theophylline, Theobromine

Potency of Methylxanthine in Respiratory Stimulation

Theophylline, Theobromine, Caffeine

Potency of Methylxanthine in Skeletal Muscle Stimulation

Theophylline, Theobromine, Caffeine

Potency of Methylxanthine in Diuresis

Theophylline, Theobromine, Caffeine

Potency of Methylxanthine in Coronary Dilation

Caffeine, Theophylline, Theobromine

Potency of Methylxanthine in Cardiac Stimulation

CYP

METABOLISM OF METHYLXANTHINES:

a. liver _________

b. _____________ (into uric acid)

a = ?

xanthine oxidase

METABOLISM OF METHYLXANTHINES:

a. liver _________

b. _____________ (into uric acid)

b = ?

Structure of Methylxanthines

1,3,7-Trimethylxanthine

IUPAC name of Caffeine

1,3-Dimethylxanthine

IUPAC Name of Theophylline

3,7-Dimethylxanthine

IUPAC Name of Theobromine

Structure of Caffeine

Structure of Theophylline

Structure of Theobromine

Depression

condition has been hypothesized to bebasedonthebalanced relationship between 5-HT, NE and DA neurotransmitters

TCAs (SNRI/NSRI), SSRIs, MAOIs, 5HT2 Antagonist/SRM

Antidepressant Drugs

Tricyclic Antidepressants (SNRIs/NSRIs), SSRIs, NDRI, and SARI

agents target a transporter protein: SERT (Serotonin Transporter), NET (Norepinephrine Transporter), and DAT (Dopamine Transporter)

SNRIs

Serotonin and norepinephrine reuptake inhibitors

SSRI

Selective serotonin reuptake inhibitors

NDRI

Norepinephrine and dopamine reuptake inhibotors

SARI

Serotonin antagonist and reuptake inhibitors

transporter proteins

Mechanism of Action of TCAs (SNRIs/NSRIs), SSRIs, NDRI, and SARI:

a. blocks _______________________ preventing inactivation of NTs, allowing NTs to function.

b. increased levels of ________________________________________________ relieves the signs of NT deficiency — antidepressant activity

a = ?

5-HT (serotonin), NE (norepinephrine), and DA (dopamine)

Mechanism of Action of TCAs (SNRIs/NSRIs), SSRIs, NDRI, and SARI:

a. blocks _______________________ preventing inactivation of NTs, allowing NTs to function.

b. increased levels of ________________________________________________ relieves the signs of NT deficiency — antidepressant activity

b = ?

Serotonin Reuptake Transporter (SERT)

Mechanism of Action of Selective Norepinephrine Reuptake Inhibitor (SNRIs):

• selectively blocks _______________________________________

Norepinephrine reuptake transporter (NET) and Serotonin Reuptake Transporter (SERT)

Mechanism of Action of Norepinephrine/Serotonin Reuptake Inhibitors (NSRIs):

• blocks ________________________________________________________ (binding is dependent on NE:5HT potency ratio)

anti-HAM (Histaminic-Adrenergic and Muscarinic)

TCAs (SNRI/NSRI) are known to produce “_________” effects like phenothiazines

anti-H1

Mechanism of Action of Selective Norepinephrine Reuptake Inhibitor (SNRIs) and Norepinephrine/Serotonin Reuptake Inhibitors (NSRIs):

a. sedation

b. orthostatic hypotension

c. dry mouth, constipation, blurred vision, urinary retention

a = ?

anti-α1

Mechanism of Action of Selective Norepinephrine Reuptake Inhibitor (SNRIs) and Norepinephrine/Serotonin Reuptake Inhibitors (NSRIs):

a. sedation

b. orthostatic hypotension

c. dry mouth, constipation, blurred vision, urinary retention

b = ?

anti-M1

Mechanism of Action of Selective Norepinephrine Reuptake Inhibitor (SNRIs) and Norepinephrine/Serotonin Reuptake Inhibitors (NSRIs):

a. sedation

b. orthostatic hypotension

c. dry mouth, constipation, blurred vision, urinary retention

c = ?

TCA Structure

2° N

Structure Activity Relationship of TCA:

• essential for SNRI selectivity

C3-X

Structure Activity Relationship of TCA:

• increases activity and affinity for NET & SERT

3C long ending with an amine

Structure Activity Relationship of TCA:

B-ring side chain:

a. must be ___________________________

b. ____________________________ decreases affinity for NET & SERT

a = ?

branching side chain

Structure Activity Relationship of TCA:

B-ring side chain:

a. must be ___________________________

b. ____________________________ decreases affinity for NET & SERT

b = ?

propylene

Structure Activity Relationship of TCA:

• Replacement of Ring N with ________________ = max potency

C10-C11

Structure Activity Relationship of TCA:

• _______________ double bond = increase activity

preferential NET/SERT binding

Structure Activity Relationship of TCA:

• O-replacement in C10-C11 leads to an E/Z mixture resulting to ___________________________________.

inactivation

Metabolism of TCA:

N-demethylation

a. SNRI = ____________

b. NSRI = __________________

a = ?

leads to NET inhibitors

Metabolism of TCA:

N-demethylation

a. SNRI = ____________

b. NSRI = __________________

b = ?

Atomoxetine, Duloxetine

Metabolism of TCA:

• Aromatic hydroxylation

C10

Metabolism of TCA:

CYP 2D6 hydroxylation

a. SNRI at ________

b. Clomipramine at __________

a = ?

C8

Metabolism of TCA:

CYP 2D6 hydroxylation

a. SNRI at ________

b. Clomipramine at __________

b = ?

CYP 2D6 demethylation

Metabolism of TCA

Clomipramine, Venlfaxine, Doxepin

Glucuronidation

Metabolism of TCA:

other metabolism

Desipramine

DIBENZAZEPINES TCAs - “ -PRAMINE”

• SNRI agent

Imipramine

DIBENZAZEPINES TCAs - “ -PRAMINE”

• NSRI prototype drug

Closmipramine

DIBENZAZEPINES TCAs - “ -PRAMINE”

• NSRI agent

Structure of Desipramine

Structure of Imipramine

Structure of Clomipramine

Nortriptyline

DIBENZOCYCLOHEPTADIENE TCAs - “ -TRIPTYLINE”

• SNRI Agent

• has N5-C12 double bond

Protriptyline

DIBENZOCYCLOHEPTADIENE TCAs - “ -TRIPTYLINE”

• SNRI Agent

• C10-11 double bond

Amitriptyline

DIBENZOCYCLOHEPTADIENE TCAs - “ -TRIPTYLINE”

• NSRI Agent

• has a propylene moiety in the B-ring

Doxepine

DIBENZOCYCLOHEPTADIENE TCAs - “ -TRIPTYLINE”

• NSRI Agent (E/Z isomers)

• E selectively inhibits NET

• S selectively inhibits SERT

Nortriptyline Structure

Protriptyline Structure

Structure of Amitriptyline

Structure of Doxepine

Atomoxetine

NON-TCA SNRIs / NSRIs

• SNRI Agent R-enantiomer is more active

Duloxetine, Milnacipran, and Venlafaxine

NON-TCA SNRIs / NSRIs

• NSRI Agent

Structure of Atomoxetine

Structure of Duloxetine

Structure of Milnacipran

Structure of Venflaxine

Electronegative (-X) 4-substitution

Structure Activity Relationship of Selective Serotonin Reuptake Inhibitors (SSRIs)

a. ____________________________ = essential for selectivity and affinity for SERT

b. SSRI ______________ significantly affects SERT selectivity

a = ?

stereochemistry

Structure Activity Relationship of Selective Serotonin Reuptake Inhibitors (SSRIs)

a. ____________________________ = essential for selectivity and affinity for SERT

b. SSRI ______________ significantly affects SERT selectivity

b = ?

SERT

Mechanism of Action of SSRIs:

• inhibits __________ with high affinity and selectivity

CYP isozymes

Metabolism of SSRIs:

a. highly metabolized in the liver by ________________ (especially CYP 2D6)

b. __________________________ for N-methyl SSRIs

c. ______________________ (Sertraline)

a = ?

N-demethylation

Metabolism of SSRIs:

a. highly metabolized in the liver by ________________ (especially CYP 2D6)

b. __________________________ for N-methyl SSRIs

c. ______________________ (Sertraline)

b = ?

MAO and Glucuronidation

Metabolism of SSRIs:

a. highly metabolized in the liver by ________________ (especially CYP 2D6)

b. __________________________ for N-methyl SSRIs

c. ______________________ (Sertraline)

c = ?

E isomer

In Escitalopram, ______________ is more selective than S isomer

R isomer

In Fluoxetine,

a. _____________________ is more potent

b. _____________________ has a higher affinity for SERT

a = ?

S isomer

In Fluoxetine,

a. _____________________ is more potent

b. _____________________ has a higher affinity for SERT

b = ?

Structure of Escitalopram (S-isomer) and Citalopram (R-isomer)

Structure of Fluvoxamine

Structure of Fluoxetine

Structure of Paroxetine

Structure of Sertraline

Fluvoxamine

E-isomer is essential for SERT inhibition

Paroxetine

(-)-3S,4R-isomer is more active for SERT inhibition

Sertraline

1S,4S-isomer is moreactivefor SERT inhibition

hypertensive crisis

Monoamine Oxidase Inhibitors (MAOIs) may result to _________________ (severe headache, tachycardia, diaphoresis, hyperprexia) when combined with sympathomimetics or tyramine containing food.

Monoamine Oxidase

enzyme responsible for the deamination of amines

5-HT

substrate for MAO-A

Epinephrine, NE, and DA

substrates for MAO-A and MAO-B

amphetamine

Structure Activity Relationship of Monoamine Oxidase Inhibitors:

a. some has similar structure with ___________________

b. presence of _______________________________ = increase potency

a = ?

electron-withdrawing groups

Structure Activity Relationship of Monoamine Oxidase Inhibitors:

a. some has similar structure with ___________________

b. presence of _______________________________ = increase potency

b = ?

metabolism of NE, 5-HT and DA

Mechanism of Action of Monoamine Oxidase Inhibitors

• inhibits ________________________________ = increasing conc. in the brain

Oxidation and N-acetylation

Metabolism of Monoamine Oxidase Inhibitors

Moclobemide

MAOIs:

• reversible inhibitor of MAO-A antidepressant w/o hypertensive crisis

Tranylcypromine

MAOIs:

• resembles amphetamine with “-methyl condensing with β-carbon

Phenelzine

MAOIs:

• irreversible inhibitor of the enzyme

Selegiline

MAOIs:

• selective irreversible inhibitor of MAO-B

Moclobemide Structure

Structure of Tranylcypromine

Structure of Phenelzine