ON

N

OO

O

F

Fanapt (Iloperidone)

O

NCH3

HHCl

CO2H

CO2H

Saphris (Asenapine)

Atypical AntipsychoticDibenzo-oxepino pyrroleMetabolism: N-dealkylation follow by glucuronidation (Most recovered in urineand feces) Uses : Schizophrenia and Bipolar depressionSide effect: Dementia in elderly

Atypical AntipyschoticPiperidinyl benzisoxazoleMetabolism: O-demethylation and carbony reductionUse: SchizophreniaSide effect: dementia in elderly

Abilify (Aripiprazole)

NH

OON

N

ClCl

NH

NN

S N

O

Cl

Geodon (Ziprasidone)

Atypical AntipsychoticDihydrocarbostyrilAdminister: po and IMPartial agonist D2 and 5HT1AAntagonist at 5HT2ASide effect: Dementia in elderlyUses: Schizophrenia, Bipolar and Autisticdisorders

Atypical AntipsychoticDihydroindoloneD2 and 5HT2A antagonistUses: Schizophrenia and BipolarSide effect: dementia in elderly

Latuda (lurasidone HCI)BenzisothiazolD2 and 5-HT2A antagonistMarketed 2010

Clinical Depression is a mood disorder in which feelings of sadness,Loss, anger or frustration interfere with daily living

SignsExpresses difficult sleeping or excessive sleepingChange in appetiteAgitation, irritabilityWithdrawnSuicidal thoughts

Common typesPostpartum depressionPremenstrual dysphoric disorder (one week before menstruation)Seasonal Affective Disorder (SAD) (Fall-Winter ends Spring-Summer)

Antidepressants (MAOI, Monoamine reuptake inhibitors and autoreceptor desensitizers and antagonist.

Monamine oxidase inhibitors (MAOI)

Nardil (Phenelzine sulfate) Irreversible inhibit MAO.What is the activity species?

Parnate (Tranylcypromine sulfate) Amphetamine like activity

HN

NH2H2SO4

NH2 H2SO4

Monoamine Reuptake Inhibitors (Norepi and 5HT)SAR for Tricyclic Antidepressant (TCA)Two aromatic ring with a central ringLink to amine by 2 or 3 carbon atomsTend to have high 5HT to NE reuptake blockageMonomethylated amine compounds are selective towards NE reuptakeAnticholinergic effect for dimethylated amineIt has both peripheral and central activityOverdose can be lethal

Tofranil (Imipramine hydrochloride) Lead TCAs. It is closely related to antipsychotic phenothiazinesMainly effect serotonin, Norepi and dopamine through transporters.High serotonin to Norepi uptake ratio blockage (sertonin reuptake inhibitor (SERI).Weak D2 postsynaptic antagonismAnticholinergic and sedative effects (blocking H1 in brain)Metabolism oxidation at 2 follow by glucuronidation

Imipramine (NSRI)

N

N

CH3

CH3

1

2

34

56

7

8

9 1011

Elavil (Amitriptyline hydrochloride) Most anticholinergic and sedative effects of TCA(NSRI)Metabolism at 10 position (hydroxylation) and at 5 position followed by conjugation.N-demethylation occurs resulting in a metabolite with less anticholinergic and sedative effect but more stimulation. Its metabolite is a selective norepinephrine reuptake inhibitor, Aventyl (SNRI).

Anafranil (Clomipramine hydrochloride) 50 times more potent imipramineIncrease in CNS penetrationUse obsessive-compulsive disorder, antianxiety and antidepressantProtonated form believe to appear beta arylamine(NSRI)

N

N

CH3

CH3

1

2

34

56

7

8

9 1011

Cl

N

CH3

CH3

1

2

34

56

7

8

9 1011

Adapin, Sinequan (Doxepin hydrochloride)Norepi and 5-HT reuptake blocker.The Z isomer is the more active. It is marketed as a mixture.Anticholinergic and sedative effects(NSRI)

Cymbalta (S-(+)-Duloxetine)(NSRI)

O

N

CH3

CH3

1

2

34

56

7

8

9 1011

HCl

S O

H

HNCH3

Selective Norepinephrine reuptake inhibitors (SNRIs)

Norpramin (Desipramine hydrochloride) Selective norepinephrine reuptake inhibitor (SNRI)Active metabolite of imipramineDecrease in anticholinergic and sedative effectMetabolism 2 –hydroxylation follow by gluc.

Aventyl (Nortriptyline hydrochloride) Selective Norepinephrine reuptake inhibitor (SNRI)Active metabolite of amitriptyline.Metabolism: N-demethylation, 10-hydroxylation

N

N

H

CH3

1

2

34

56

7

8

9 1011

N

H

CH3

1

2

34

56

7

8

9 1011

Vivactil (Protriptyline hydrochloride) Relocation of double when compared with Aventyl(SNRI)

Surmontil (Trimipramine Maleate) Marketed as a racemicActivity similar to Tofranil(SNRI)

N

H

CH3

1

2

34

56

7

8

9 1011

N

N

CH3

CH3

CH3

Asendin (Amoxapine)DibenzoxazpinAntidepressant/antipsychoticActive metabolite of loxapineD2 receptor antagonism(SNRI)

Vestra (Reboxetine)S,S, isomer is the active one (marketed enantiomeric mixture) Europe(SNRI)

N

O

N

NH

Cl

O

O

O

HN

Ludiomil (Maprotiline HCl)Tetracyclic compoundLow anticholinergic effectsCNS StimulationMetabolism N-demethylation (active metabolite)(SNRI)

Strattera ( R-Atomoxetine)Marketed as non-stimulant forADD (2003)R-enantiomer (10 x more potentthan S isomer)Similar to Prozac in structure.(SNRI)Metabolism N-demethylationanother route p-hydroxylationFollow by gluc.

NH

O

HN

CH3

CH3

NisoxetineUse as antidepressantIn Europe(SNRI)

O

O

NH

Prozac (Fluoxetine)Protonate it can for a pseudo ring.S isomer is more selective for SERT than Norepi transporter (NET) proteinMovement of para substituent to orthro produce selective norepinephrine reuptake inhibitors.2 or more weeks are required before antidepressant effect (desensitization of 5HT1A autoreceptor).Use for depression and anxiety(SSRI)

Paxil (3S, 4R -Paroxetine)Contrained analogue of ProzacVery highly selective for SERT.(SSRI)Metabolism: formation ofCatechol follow by gluc.

Selective Serotonin Reuptake inhibitors (SSRIs)Structural differ than tricyclics in that tricyclic has been separate.Competitive inhibition of Sertonin transporter protein (SERT)Little anticholinergic activity by breaking ring structure

O NHCH3

CF3

NH

F

O

O

O

Zoloft (Sertraline) (1S, 4S) structureStereochemistry is important for activity(SSRI)Metabolism: N-demethylation

Luvox (Fluvoxamine)Nontricyclic SERT inhibitorE isomer Protonated folds back to form a pseudo ringProtected from light (convert Z-isomer)(SSRI)

Cl

Cl

NHCH3HCl

CF3

N

OCH3

O

NH2

Lexapro (S-Escitalopram)No advantage giving pure isomerCelexa is racemic mixtureMetabolism: N-demethylation to activemetabolite(SSRI)

O

(CH2)3N(CH3)2

NC

F

Nontricyclic Nonselective Norepi and 5-HT reuptake inhibitors

Effexor (Venlafaxine)Resemble open TCAMetabolism: O-demethylation (activemetabolite)NSRI

Selective Serotininergic Reuptake inhibitors and 5HT2A Antagonists

Desyrel (Trazodone)Metabolism: N-Dealkylation to m-chloropiperazine active metabolite

N

O

OH NN

N

N

N

Cl

O

HCl

Serzone (Nefazodone) Structure similar to fluorobutyrophenone antipsychotics.Bind to SERT and active as 5HT2A Antagonists.What metabolite is generated for both of the drugs?

5HT1A Agonists and Partial Agonists

BuSpar (Buspirone)Partial 5HT1A agonist (decrease release of 5HT) (antianxiety)Postsynaptic receptors stimulation (anti-depressive)

NN

N

N

N

Cl

O

HCl

O

N N

N

N

N

O

O

Miscellaneous Antidepressant

Wellbutrin (Bupropion) Complex mechanism involving dopamine transporter protein (DAT) and as well as norepireuptake.What is the cyclic metabolite responsible for its activity?

Remeron (Mirtazpine)a2-antagonist/serotonin antagonistMetabolism: N-demethylationAnd hydroxylation of pyridine (8-position)

Cl

O

NH

N N

NCH3

Other Treatments for Clinical Depression

Lithium carbonate treat manic depression (mood stabilizer)

Electroconvulsive therapy effect gold standard for treatment of major depression

Herbal therapy (St. John Wort) works like SSRI

Structure of Key Neurotransmitters

HO

HO

NH2 HO

HO

NH2OH

NH

NH2

HO

DopamineNorepinephrine

Serotonin

N

HO

OH CO2H

CO2H

H2O

Pristiq (desvenlafaxine)This a metabolite of which drug?Approved as antidepressant February of 2008

New Antidepressant

Future class of Antidepressant called TRI