Medicinal Chemistry 5210 - Fall 2006 - Davis Section.
http://www.pharmacy.utah.edu/medchem/faculty/davis/mdch5210.html
darrell.davis@hsc.utah.edu - Office: BPRB 295E - Phone: 581-7006
Reading List (Foye’s Principles of Medicinal Chemistry, Fifth Edition)
1- CNS Stimulants (3 lectures - Foye Ch. 12,18)
2- Neuroleptic Antipsychotics (2 lectures - Foye Ch. 17)
3-Opioid Analgesics (3 lectures - Foye Ch. 19)
Exam ()
4- Anticonvulsants (2 lectures - Foye Ch. 16)
5- Antihistamines (2 lectures - Foye Ch. 33)
6- General Anesthetics (1 lecture - Foye Ch. 14)
7-Local Anesthetics (1 lecture - Foye Ch. 13)
Old Exams - Available on the Web Page.
Exam ()
Lectures - PPT files available on the Web Page.
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Davis MDCH 5210 - CNS Stimulants, 2006
CNS Stimulants
Therapeutic Treatment for: Depression, Narcolepsy, Obesity
Analeptic - A CNS stimulant that causes muscle contraction and perhaps also
convulsions. Particularly a term used to describe compounds that cause
contraction and rigidity of the muscles of respiration. Strychnine is the most
commonly recognized analeptic although it has relatively low potency.
Mechanisms of Action for CNS Stimulants:
1.
Block neurotransmitter reuptake (Most reuptake inhibitors affect either
NE or 5HT)
Tricyclic antidepressants
Cocaine
Selective Serotonin reuptake inhibitors
2. Promote Neurotransmitter Release
Phenylethylamines and related compounds. Amphetamine,
Methylphenidate.
3. Block Metabolism - MAO inhibitors
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Davis MDCH 5210 - CNS Stimulants, 2006
Non-Therapeutic CNS stimulants
(all seizure inducers)
Strychnine - Inhibits glycine receptors
Picrotoxin - Acts on the chloride ion channel associated
with GABA receptors.
Bemigride - Barbiturate Antagonist
Pentylene tetrazole - Na+/K+ channel blocker?
Increases cholinergic activity.
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Davis MDCH 5210 - CNS Stimulants, 2006
Xanthines (Caffeine, theophylline, theobromine)
Mechanism(s) of action:
•Inhibition of cAMP phosphodiesterase
•Competitive inhibitor of adenosine
•Promote NE release
•Promote intracellular Ca+2 release
O
CH3
N
O
N
CH3
N
O
N
H
O
Theophylline
N
NH 2
CH3
N
N
N
CH3
Caffeine
O
H
N
N
CH3
The order of potency for CNS activity is
Caffeine > Theophylline > Theobromine
Theophylline is an important drug for maintenance
treatment of asthma,
but has some side effects as you might expect.
N
O
CH3
N
N
N
N
H
CH3
Theobromine
N
Adenine
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Davis MDCH 5210 - CNS Stimulants, 2006
Phenylethylamines
•Enhance neurotransmitter release
•Block NT reuptake
•Have direct agonist effects
•MAO inhibition
Phenylethylamines are used as anorectics, for narcolepsy, and ADHD. Not
legitimate antidepressants.
The SAR is relatively well-defined as we learned for the indirect acting NE
agonists. The phenyl ring and the distance between the amine and the
phenyl is fairly strict. For the phenidates, the SAR of methyl phenidate is
optimal. Changes that affect the rate of methyl ester hydrolysis affect
duration and potency.
With the exception of anorexia, many of the CNS effect of
phenylethylamines are thought to involve effects on dopamine release and
reuptake.
“Amphetamine induces dopamine efflux through a dopamine transporter channel”
PNAS (2005) vol. 102 |3495-3500
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Davis MDCH 5210 - CNS Stimulants, 2006
Amphetamine Structures
CH2 CH NH 2
CH3
O
C OCH3
Amphetamine
Prototype phenylethylamine. The good, the bad,
and the ugly
Methylphenidate
(Ritalin)
Used for attention-deficit-hyperactive disorder
Usually in children
CH
N
H
O
N
H3 C
H
Phenmetrazine
(Preludin)
Anorectic
O
Phendimetrazine (Plegine)
Anorectic
N
H3 C
CH3
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Davis MDCH 5210 - CNS Stimulants, 2006
Neuronal Synapse - NE Mechanism
Goodman and Gilman, 9th Edition
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Davis MDCH 5210 - CNS Stimulants, 2006
Neuronal Synapse - 5HT
5-HT1A
Tryptophan
TPH
Tryptophan
LNAA
5-HTP
AADC
Pre-synaptic
5-HT
5-HIAA
MAO
5-HT
5-HT1B
SERT
5-HT2A
5-HT1A
5-HT2c
Post-synaptic
5-HT1B
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Davis MDCH 5210 - CNS Stimulants, 2006
Halogen Substituted Phenylethylamines.
“The Halogen Rule ™”
Halogen substitutions provide for 5HT selectivity/specificity. The
halogen rule, also applies to reuptake inhibitors.
CH 3
CH3
Cl
CH2 CH NH2
CH2 CH NH
CH2 CH NH 2
CH3
CH3
F3C
4-chlorophenylethylamine
(5HT selective)
Phentermine
(DA selective)
Fenfluramine
(5HT selective)
NH 2
HO
N
H
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Davis MDCH 5210 - CNS Stimulants, 2006
A few thoughts on Anorectics.
Regulation of food intake is a complicated process. Pretty much all of
the major CNS neurotransmitter systems have been implicated.
However, direct injection of serotonin reduces food intake, and
fenfluramine requires an intact serotoninergic system for its anorectic
effects.
A problem is that reduction in food intake is usually accompanied by a
feeling of hunger. Addressing this was the promotion of the theory
that increasing serotonin levels while simultaneously increasing
dopamine levels would be beneficial.
Increased DA would reduce the feelings of hunger. Therefore
Phentermine with Fenfluramine.
Don’t quite understand how you reduce food intake, without diminishing
hunger, but there you have it.
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Davis MDCH 5210 - CNS Stimulants, 2006
Ashcraft
&
Gerel LLP
Fen-Phen Lawsuits - Many
The Victims' Rights Law Firm
Washington, D.C.
Maryland
(Baltimore
Landover
Rockville)
Virginia
FEN-PHEN DIET DRUG LITIGATION - FREQUENTLY ASKED QUESTIONS
Introduction
What should I do medically if I used these drugs?
What is Fen-Phen?
What is Redux?
What Heart Valve Problems are caused by these drugs?
What is Primary Pulmonary Hypertension?
What types of Neurotoxicity are associated with these drugs?
What can I do legally to protect myself?
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Davis MDCH 5210 - CNS Stimulants, 2006
Clinical and Echocardiographic Follow-up of Patients Previously Treated With Dexfenfluramine or
Phentermine/Fenfluramine
Julius M. Gardin, MD; Neil J. Weissman, MD; Cyril Leung, MD; Julio A. Panza, MD; Daniel Fernicola, MD; Kelly D. Davis,
MD; Ginger D. Constantine, MD; Cheryl L. Reid, MD
JAMA. 2001;286:2011-2014.
Did Phen/Fen cause heart valve damage?
Maybe - Was there long term damage?
ABSTRACT
Context Use of anorexigen therapy is associated with valvular abnormalities, although there is limited information on
long-term changes in valvular regurgitation following discontinuation of these agents.
Objective To evaluate changes in valvular regurgitation, valve morphology, and clinical parameters 1 year after an initial
echocardiogram in patients previously treated with dexfenfluramine or phentermine/fenfluramine and in untreated
controls.
Design and Setting A reader-blinded, multicenter, echocardiographic and clinical 1-year follow-up study at 25 outpatient
clinical sites.
Patients A total of 1142 obese patients (1466 participated in the initial study) who had follow-up echocardiogram; all but
4 had a follow-up medical history and physical examination. Follow-up time from discontinuation of drug to follow-up
echocardiogram for 371 dexfenfluramine patients was 17.5 months (range, 13-26 months) and for 340
phentermine/fenfluramine patients was 18.7 months (range, 13-26 months) after discontinuation of drug therapy.
Main Outcome Measure Change in grade of valvular regurgitation and valve morphology and mobility.
Results Echocardiographic changes in aortic regurgitation were observed in 8 controls (7 [1.7%] had decreases; 1
[0.2%] had an increase); 29 dexfenfluramine patients (23 [6.4%] had decreases; 6 [1.7%] had increases; P<.001 vs
controls); and 15 phentermine/fenfluramine patients (4.5% all decreases; P = .03 vs controls). No statistically
significant differences were observed when treated patients were compared with controls for changes in
medical history, physical findings, mitral regurgitation, aortic or mitral leaflet mobility or thickness, pulmonary
artery systolic pressure, ejection fraction, valve surgery, or cardiovascular events.
Conclusion: Progression of valvular abnormalities is unlikely in patients 1 year after an initial echocardiogram
and 13 to 26 months after discontinuation of dexfenfluramine and phentermine/fenfluramine
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Davis MDCH 5210 - CNS Stimulants, 2006
The Good -old Days
of Antidepressants
Dexamyl: Dextroamphetamine + amobarbital
A better one was “Desbutal” : methamphetamine and pentobarbital
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Davis MDCH 5210 - CNS Stimulants, 2006
Monamine Oxidase (MAO) Inhibitors
Two MAOs, MAO-A and MAO-B.
Selective MAO-B inhibitors increase levels of dopamine in the brain,
therefore may be useful for Parkinson’s disease.
MAO inhibitors are sometimes used as antidepressants, when patients don’t
respond to the tricyclics. There are “atypical” cases of depression that
respond to MAO inhibitors, but not to tricyclics or electroshock therapy.
Mechanism of Action. Elevate levels of most monamine neurotransmitters.
However, the antidepressant effects take 2-4 weeks to manifest. This
suggests that adaptive changes in receptors, or the balance of NT levels are
responsible for the antidepressant effects. For instance -adrenergic
receptors appear to be down-regulated. Also, increased DA levels may lead
to increased intracellular NE levels over and above the increases as a direct
result of MAO inhibition. Complicated stuff.
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Davis MDCH 5210 - CNS Stimulants, 2006
MAO SAR
MAO SAR
Primary sites of binding are the side chain amine and the aromatic group.
Electron withdrawing groups increase potency. For the irreversible compounds,
a reactive hydrazine, cyclopropyl, or acetylene (alkynyl) group is present.
RIMAs (reversible inhibitors of MAO) don’t have this.
The enzyme is stereoselective as indicated by the preference (3-fold) of the
trans vs. cis tranylcypromine (Parnate) compounds. There is that rigid analog
thing again. The two enantiomers of amphetamine also show different levels of
inhibition of MAO.
H
O
N
N
NH 2
CH3
N
H
Iproniazid
1st generation
Irreversible, non-selective
CH3
Tranylcypromine
(Parnate)
1st generation
N
C
CH
Selegiline
(Eldepryl)
2nd Generation
Irreversible, MAO-B
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Davis MDCH 5210 - CNS Stimulants, 2006
Tricyclic Antidepressants
The “amine theory of depression.”
Drugs that increase the levels of amine neurotransmitters are potential
antidepressants. Does depression arise due to abnormally low levels of amine
neurotransmitters?
Most antidepressants, especially the first generation drugs increase the levels of
amines. The effect on amine NT levels is immediate. However, the
antidepressant effects take 1-2 weeks to become apparent.
Therefore focus has shifted somewhat to adaptive effects in receptor systems,
primarily the -adrenergic receptors and their associated cAMP second
messengers systems, but pretty much the entire list of adrenergic,
serotoninergic, DA, GABA, etc. systems. Partially out of recognition that these
are often intertwined.
cAMP production is stimulated, then an adaptive decrease in adrenergic receptor
sites occurs, ultimately decrease the levels of adenylate cyclase and cAMP.
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Davis MDCH 5210 - CNS Stimulants, 2006
The pharmacology of putative early-onset antidepressant strategies
Blier, P. Eur Neuropsychopharmacol. 2003 Mar;13(2):57-66
Abstract:
Depression is a serious and burdensome illness. Although selective serotonin
reuptake inhibitors (SSRIs) have improved safety and tolerability of antidepressant
treatment efficacy, the delay in the onset of action have not been improved. There is
evidence to suggest that the delay in onset of therapeutic activity is a function of the
drugs, rather than the disease. This suggests that research into the biological
characteristics of depression and its treatments may yield faster-acting
antidepressants. Emerging evidence from clinical studies with mirtazapine,
venlafaxine and SSRI augmentation with pindolol suggests that these treatments
may relieve antidepressant symptoms more rapidly than SSRIs. The putative
mechanism of action of faster-acting antidepressant strategies presented here
purports that conventional antidepressants acutely increase the availability of
serotonin (5-hydroxytryptamine, 5-HT) or noradrenaline (NA), preferentially at their
cell body level, which triggers negative feedback mechanisms. After continued
stimulation, these feedback mechanisms become desensitised and the enhanced 5HT availability is able to enhance 5-HT and/or NA neurotransmission. Putative fastonset antidepressants, on the other hand, may uncouple such feedback control
mechanisms and enhance 5-HT and/or NA neurotransmission more rapidly. Further
studies are required to characterise in detail the interactions between NA and 5-HT
systems and to definitively establish the early onset of candidate antidepressants
such as mirtazapine, venlafaxine and pindolol augmentation.
Davis MDCH 5210 - CNS Stimulants, 2006
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Tricyclic Antidepressant SARThe first generation compounds have a central, tricyclic ring stucture. The
three-dimensional structure is thought to be important, with a puckered, nonplanar structure distinguishing antidepressants from related compounds such as
the antipsychotic, post-synaptic dopamine antagonists.
Short amine side chains are important for the older and newer antipsychotics..
Monomethyl amines are more potent than dimethylamines as shown for
imipramine and desipramine.
Ring substitutions have little effect on NE and dopamine activity, Halogen
substitution does not increase activity and is not necessary for DA tricyclic
activity as seen for the closely related DA antagonists.
The Halogen Rule, Again.
Halogen substituted compounds are generally more selective for 5HT receptors.
Although the selective serotonin compounds are often not tricyclic, they can
adopt a similar conformation and do show cross-reactivity with DA and NE sites.
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Davis MDCH 5210 - CNS Stimulants, 2006
Representative Tricyclic Structures. (The important ones)
N
N
CH2 CH2 CH2 N(CH3)2
CH2CH2 CH2 NHCH 3
Imipramine (Tofranil)
Desipramine (Pertrofrane)
F3 C
O CH
O CH
CH2 CH2NHCH 3
Fluoxetine (Prosac)
H3C
CH2 CH2 NHCH 3
O
Nisoxetine
Br
N
N
CHCH 2 N(CH3)2
Zimeldine (Zelmid)
Cl
CH2 CH2 CH2 N(CH3 )2
Clomipramine (Anafranil)
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Davis MDCH 5210 - CNS Stimulants, 2006
IC-50’s of 5-HT/NE/DA Reuptake Inhibitors
Zoloft
Paxil
Lower IC50 means greater receptor affinity
High NE/5-HT - more selective for 5-HT
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Davis MDCH 5210 - CNS Stimulants, 2006
F3 C
O
O
CH
CH 2CH2 NHCH3
H3 C
Fluoxetine (Prosac)
CH
CH 2CH2 NHCH3
O
Nisoxetine
Reuptake Inhibito
Structures
Br
N
N
Cl
CH2CH2CH 2N(CH3) 2
CHCH2N(CH3 )2
Zimeldine (Zelmid)
Clomipramine (Anafranil)
O
F3 C
O
O
H2 C
(CH2 )4OCH3
N
F
NH
O(CH 2)2 NH2
Paroxetine (Paxil)
Fluvoxamine (Luvox)
CH3
O
Cl
NHCH 3
Cl
CH3
N
H
Sertraline (Zoloft)
Atomoxetine (Strattera)
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Davis MDCH 5210 - CNS Stimulants, 2006
Miscellaneous CNS Stimulants - Hallucinogens
Mechanism of Action -(The usual)
Phenylethylamines promote NT release and inhibit MAO. The hallucinogenic
effects probably are due to 5HT activity.
The simple indole alkaloids probably have similar actions, though may have
specificity for 5HT sites.
More complex indoles have high affinity for 5HT receptors and have full or
partial agonist activity.
O
NH2
HO
N
H
OH
NH2
N
H
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Davis MDCH 5210 - CNS Stimulants, 2006
Aldous Huxley Had the Answer
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Davis MDCH 5210 - CNS Stimulants, 2006
Hallucinogen Structures
CH3 O
NH 2
OH
N(CH 3 )2
CH3 O
OCH3
N
Mescaline
(a phenylethylamine)
H
Psilocin
(31 Mescaline Units)
O
CH3 CH2
CH3 O
NH
N
H
N
CH3 CH2
N
H
CH3
Tetrahydroharmine
(An indole alkaloid)
Similar to Mescaline in potency
100 mg Hallucinogenic dose
Mescaline ~300 mg dose
LSD ~3000 MUs
CH3
NH
Lysergic Acid Diethylamide
LSD-25
100 g Hallucinogenic dose
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Davis MDCH 5210 - CNS Stimulants, 2006
SAR for Phenylethylamine Hallucinogens, Stimulants
OCH 3
NH 2
NHCH3
NH 2
CH3
CH3
CH3
O
O
H3C
Amphetamine
OCH 3
(S)
DOM
(H)
O
MDMA
(O)
OH
NHCH3
NH 2
CH3
Cathinone
(S)
CH3
Ephedrine, pseudoephedrine
(S)
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Davis MDCH 5210 - CNS Stimulants, 2006
Phenylisopropylamines
NHCH3
CH3
O
O
MDMA
(O)
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Davis MDCH 5210 - CNS Stimulants, 2006
Attention Deficit Hyperactive Disorder – ADHD
CH 2 CH NH 2
CH 3
O
C OCH 3
CH
N
Amphetamine
Dextroamphetamine (Adderall, Dexedrine)
Methylphenidate
(Ritalin)
H
Treatments – The most widely used is Methylphenidate, followed by
dextroamphetamine, tricyclic antidepressants.
What is the “cause”?
ADHD has a strong inheritance link. Children with ADHD often have siblings
with the disorder, other relatives, and appear to inherited a predisposition for
the disorder.
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Davis MDCH 5210 - CNS Stimulants, 2006
Dopamine Receptors and ADHD
The dopamine D4 receptor, DRD4, gene seems to be linked with
inheritance patterns for ADHD.
The DRD3 and DRD5 genes show no linkage. That is, heritance patterns
of these genes and ADHD are not correlated.
Other possible neuronal systems that play a role in ADHD include
serotonin HTR2A and SNAP-25 which is a protein involved in vesicle
fusion. Mice with SNAP-25 mutants are spontaneously hyperactive, but
respond to dextroamphetamine.
Mol. Psychiatry (2000) 5, 405 (snap-25)
Mol Psychiatry (2000) 5, 537 (HTR2A)
J Clin Psychiatry. 2006;67 Suppl 8:13-20. Candidate gene studies of
attention-deficit/hyperactivity disorder
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Davis MDCH 5210 - CNS Stimulants, 2006
Do we understand what causes ADHD?
What does this mean?
Methylphenidate (Ritalin) treatment is controversial
Dextroamphetamine (Adderall) treatment is probably more controversial
Clinical Trials (Evid. Rep. Tech. Asses. (1999) 11, 1-341) indicate that
methylphenidate and dextroamphetamine are probably the most effective
treatments, better than tricyclic antidepressants, although desipramine may be
beneficial.
Successful ADHD treatment with MPH is consistent with the D4 receptor gene
alleles showing co-inheritance with ADHD.
Previous DAT1, DA transporter linkage is not supported, but serotonin 2A
receptors do show linkage.
Finally:
There seem to be an emerging consensus that ADHD has a genetic component,
there are specific receptors involved, the disorder responds to stimulants, and
this response is consistent with the receptors.
The challenge would then be to correctly diagnose the disorder, and to also
develop new drugs that are more selective.
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Davis MDCH 5210 - CNS Stimulants, 2006
F3 C
O
O
CH
CH 2CH2 NHCH3
H3 C
Fluoxetine (Prosac)
CH
CH 2CH2 NHCH3
O
Reuptake Inhibitors - Again
Nisoxetine
Br
N
N
Cl
CH2CH2CH 2N(CH3) 2
CHCH2N(CH3 )2
Zimeldine (Zelmid)
Clomipramine (Anafranil)
O
F3 C
O
O
H2 C
(CH2 )4OCH3
N
F
NH
Can you see the SAR (structural) similarity
between fluoxetine, paroxetine, sertraline,and
atomoxetine?
O(CH 2)2 NH2
Paroxetine (Paxil)
Fluvoxamine (Luvox)
CH3
O
Cl
NHCH 3
Cl
CH3
N
H
Sertraline (Zoloft)
Atomoxetine (Strattera)
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Davis MDCH 5210 - CNS Stimulants, 2006
Newer Antidepressants – Additional Mechanisms of Action
N
CH3
N
N(CH 3)2
N
N
CH3
Trimipramine (Surmontil)
Mirtazapine (Remeron)
Cl
N
N
N
N
N
O
Cl
O
N
N
N
N
N
OPh
CH2 CH3
Trazodone (Desyrel)
Nefazodone (Serzone)
Conventional antidepressants acutely increase the availability of NA and 5HT,
triggering negative feedback mechanisms. This feedback becomes desensitized
with time and the enhanced availability of 5HT, primarily, enhances 5HT
neurotransmission. Fast-onset antidepressants, in contrast, uncouple the
feedback (inhibit 2 autoreceptors for example) and have a more immediate
effect.
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Davis MDCH 5210 - CNS Stimulants, 2006
Some of the New(er) Guys
•Mirtazapine (Remeron) Presynaptic 2-antagonist – Acts to increase the levels of both
NA and 5HT. Additionally blocks post-synaptic 5HT2 and 5HT3 receptors, without
affecting 5HT1. Benefits are decreased side effects and more immediate antidepressant
action.
•Trimipramine (Surmontil) Supposedly is both an antipsychotic like clozapine and an
antidepressant. Despite the “tricyclic” structure, it does not have significant reuptake
inhibition activity. Mechanism is sketchy
•Nefazodone (Serzone) 5HT2A (serotonin) antagonist and modest NA and 5HT reuptake
inhibitor (SARI). Structurally unrelated to other antidepressants, but chemical similar to
butyrophenone antipsychotics.
•Trazodone (Desyrel) May also be a SARI
•Atomoxetine (Strattera) SNRI – Serotonin/Norepinephrine reuptake inhibitor. Newer
treatment for ADHD.
•Venlafaxine (Effexor) SNRI
•Bupropion (Wellbutrin) NDRI - Norepinephrine/Dopamine
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Davis MDCH 5210 - CNS Stimulants, 2006
Mechanisms of Antidepressants:
Mechanisms of Antidepressants:
NA & DA RI (NDRI)
5-HT1A
Tryptophan
TPH
Tryptophan
LNAA
5HT2A antagonist, NA & 5HT RI (SARI).
5-HTP
2 antagonist, NA & 5HT RI
AADC
Pre-synaptic
Serotonin/NA RI (SNRI)
5-HT
5-HIAA
MAO
5-HT
5-HT1B
SERT
5-HT2A
5-HT1A
5-HT2c
Post-synaptic
5-HT1B
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Davis MDCH 5210 - CNS Stimulants, 2006
Venlafaxine/Bupropion Structures
Venlafaxine (Effexor) SNRI
Bupropion (Wellbutrin) NDRI
Norepinephrine/Dopamine
These are structurally unrelated to other tricyclics and perhaps are
Mechanistically distinct.
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Davis MDCH 5210 - CNS Stimulants, 2006