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