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					                    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)

                                          Exam ()
Old Exams - Available on the Web Page.    Lectures - PPT files available on the Web Page.




                                                                                                                  1
                                                                         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

                                                                                                2
                                                       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.




                                                                                    3
                                           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       CH 3                           O       H
                                                    CH 3              N                    CH 3
                                                           N                                                 N
                                                                                                  N

                                                      O        N      N                                      N
                                                                                              O       N
                                                               CH 3                                   CH 3
The order of potency for CNS activity is
Caffeine > Theophylline > Theobromine                      Caffeine                                Theophylline
Theophylline is an important drug for maintenance
treatment of asthma,                                           O
                                                                                                      NH 2
                                                                      CH 3
but has some side effects as you might expect.        H                                                      N
                                                                      N                           N
                                                           N

                                                                                                      N      N
                                                      O        N      N
                                                                                                             H
                                                               CH 3


                                                           Theobromine                             Adenine

                                                                                                                   4
                                                                          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


                                                                                               5
                                                      Davis MDCH 5210 - CNS Stimulants, 2006
Amphetamine Structures
    CH2 CH NH 2
                        Amphetamine
         CH 3           Prototype phenylethylamine. The good, the bad,
                        and the ugly

O
    C OCH3
                        Methylphenidate
    CH
                        (Ritalin)
               N        Used for attention-deficit-hyperactive disorder
           H            Usually in children


           O
                         Phenmetrazine
                N        (Preludin)
                         Anorectic
    H3 C            H



       O
                        Phendimetrazine (Plegine)
           N            Anorectic
H3 C            CH 3




                                                                                                   6
                                                          Davis MDCH 5210 - CNS Stimulants, 2006
Neuronal Synapse - NE Mechanism




  Goodman and Gilman, 9th Edition




                                                                             7
                                    Davis MDCH 5210 - CNS Stimulants, 2006
                   Neuronal Synapse - 5HT
                    Tryptophan             Tryptophan
          5-HT1A                     LNAA
                           TPH

                      5-HTP
                          AADC
Pre-synaptic
                      5-HT                     5-HIAA


                                     MAO

                              5-HT
                                             5-HT1B


                             SERT



               5-HT1A         5-HT2c
   5-HT2A                                   5-HT1B
                    Post-synaptic

                                                                                                 8
                                                        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                                     CH 3
     Cl              CH 2 CH   NH 2           CH 2 CH     NH 2              CH 2CH     NH
                                                   CH 3                         CH 3
                                                                  F3C
          4-chlorophenylethylamine         Phentermine                  Fenfluramine
          (5HT selective)                  (DA selective)               (5HT selective)


                                      HO                         NH 2


                                               N
                                               H




                                                                                                                        9
                                                                               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.


                                                                                               10
                                                      Davis MDCH 5210 - CNS Stimulants, 2006
Ashcraft                          Fen-Phen Lawsuits - Many
&
Gerel LLP
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?
                                                                                                        11
                                                               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,

                                   Did Phen/Fen cause heart valve damage?
MD; Ginger D. Constantine, MD; Cheryl L. Reid, MD


                                    Maybe - Was there long term damage?
JAMA. 2001;286:2011-2014.

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
                                                                                                                                  12
                                                                                         Davis MDCH 5210 - CNS Stimulants, 2006
  The Good -old Days
  of Antidepressants




Dexamyl: Dextroamphetamine + amobarbital
A better one was “Desbutal” : methamphetamine and pentobarbital
                                                                                                           13
                                                                  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.




                                                                                               14
                                                      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.



                  O       H                          NH 2
                                                                           CH 3
                          N
                      N
                                                                       N          CH
         N            H                                          CH3         C



         Iproniazid                    Tranylcypromine      Selegiline
         1st generation                (Parnate)            (Eldepryl)
         Irreversible, non-selective   1st generation       2nd Generation
                                                            Irreversible, MAO-B


                                                                                                            15
                                                                   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.




                                                                                                 16
                                                        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 5-
HT availability is able to enhance 5-HT and/or NA neurotransmission. Putative fast-
onset 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.
                                                                                                      17
                                                             Davis MDCH 5210 - CNS Stimulants, 2006
                         Tricyclic Antidepressant SAR-


The first generation compounds have a central, tricyclic ring stucture. The
three-dimensional structure is thought to be important, with a puckered, non-
planar 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.



                                                                                                  18
                                                         Davis MDCH 5210 - CNS Stimulants, 2006
Representative Tricyclic Structures. (The important ones)



                       N                                N
                       CH2 CH 2 CH 2 N(CH3)2            CH 2CH 2 CH 2 NHCH 3


              Imipramine (Tofranil)            Desipramine (Pertrofrane)


       F3 C



                      O CH                                      O CH
                           CH 2 CH 2NHCH 3       H3C        O       CH 2 CH 2 NHCH 3


              Fluoxetine (Prosac)                        Nisoxetine

                                      Br

              N
                                                                N
                                                                              Cl
                      CHCH 2 N(CH3)2                            CH2 CH 2 CH 2 N(CH3 )2


              Zimeldine (Zelmid)                    Clomipramine (Anafranil)
                                                                                                              19
                                                                     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




                                                                                                   20
                                                          Davis MDCH 5210 - CNS Stimulants, 2006
F3 C



                  O   CH                                        O       CH                  Reuptake Inhibito
                                                                                               Structures
                      CH 2CH2 NHCH3                                     CH 2CH2 NHCH3
                                                    H3 C    O


         Fluoxetine (Prosac)                                Nisoxetine

                                  Br

        N
                                                                  N
                                                                              Cl
                  CHCH2N(CH3 )2                                   CH2CH2CH 2N(CH3) 2


         Zimeldine (Zelmid)                            Clomipramine (Anafranil)


                                                                                       O
  F3 C
                                                                    O                  O
                                                           H2 C
                          (CH2 )4OCH3
                                                F                            NH
                      N
                          O(CH 2)2 NH2




         Fluvoxamine (Luvox)                         Paroxetine (Paxil)

                                                            CH3



                                                                O
   Cl                                  NHCH 3
                                                                                      CH3
                                                                                  N
                                                                                  H
         Cl


            Sertraline (Zoloft)
                                                       Atomoxetine (Strattera)                                                        21
                                                                                             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        OH

                                    NH2
                 HO                                            NH2

                             N
                             H                       N
                                                     H

                                                                                                  22
                                                         Davis MDCH 5210 - CNS Stimulants, 2006
Aldous Huxley Had the Answer




                                                              23
                     Davis MDCH 5210 - CNS Stimulants, 2006
                   Hallucinogen Structures
              CH 3 O                       NH 2
                                                       OH

                                                                          N(CH3 )2
               CH 3 O
                           OCH3
                                                                  N
                                                                  H
                   Mescaline
                   (a phenylethylamine)               Psilocin
                                                      (31 Mescaline Units)



                                                                  O
                                                  CH 3 CH 2                  CH 3
                                                              N         N
                                          NH                                 H
          CH 3 O             N                    CH 3 CH 2
                             H      CH 3


                                                                                 NH
              Tetrahydroharmine
              (An indole alkaloid)
              Similar to Mescaline in potency        Lysergic Acid Diethylamide
              100 mg Hallucinogenic dose             LSD-25
                                                     100 g Hallucinogenic dose
Mescaline ~300 mg dose
LSD ~3000 MUs
                                                                                                               24
                                                                      Davis MDCH 5210 - CNS Stimulants, 2006
SAR for Phenylethylamine Hallucinogens, Stimulants




                             OCH 3
                                                                            NHCH3
              NH 2
                                         NH 2
                                                                         CH3
         CH3
                                      CH3               O
                       H3C                                    O
Amphetamine
                             OCH 3
   (S)                                                            MDMA
                             DOM                                  (O)
         O                   (H)            OH

                NH 2                                  NHCH3


              CH3                                CH3

                                Ephedrine, pseudoephedrine
 Cathinone                                      (S)
   (S)
                                                                                                     25
                                                            Davis MDCH 5210 - CNS Stimulants, 2006
                          Phenylisopropylamines




                 NHCH3


               CH3
O
    O

        MDMA                                             26
        (O)     Davis MDCH 5210 - CNS Stimulants, 2006
                Attention Deficit Hyperactive Disorder – ADHD

                           CH 2 CH NH 2   Amphetamine
                                CH 3      Dextroamphetamine (Adderall, Dexedrine)


                       O
                           C OCH 3
                                          Methylphenidate
                           CH
                                          (Ritalin)
                                      N
                                  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.



                                                                                                            27
                                                                   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



                                                                                           28
                                                  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.


                                                                                               29
                                                      Davis MDCH 5210 - CNS Stimulants, 2006
F3 C



                  O   CH                                        O       CH

                      CH 2CH2 NHCH3                 H3 C    O
                                                                        CH 2CH2 NHCH3         Reuptake Inhibitors - Again
         Fluoxetine (Prosac)                                Nisoxetine

                                  Br

        N
                                                                  N
                                                                              Cl
                  CHCH2N(CH3 )2                                   CH2CH2CH 2N(CH3) 2


         Zimeldine (Zelmid)                            Clomipramine (Anafranil)


                                                                                       O
  F3 C
                                                                    O                  O
                                                           H2 C
                          (CH2 )4OCH3
                                                F                            NH
                      N
                          O(CH 2)2 NH2
                                                                                            Can you see the SAR (structural) similarity
                                                                                            between fluoxetine, paroxetine, sertraline,and
                                                                                            atomoxetine?
         Fluvoxamine (Luvox)                         Paroxetine (Paxil)

                                                            CH3



                                                                O
   Cl                                  NHCH 3
                                                                                      CH3
                                                                                  N
                                                                                  H
         Cl


            Sertraline (Zoloft)
                                                       Atomoxetine (Strattera)
                                                                                                                                              30
                                                                                                     Davis MDCH 5210 - CNS Stimulants, 2006
     Newer Antidepressants – Additional Mechanisms of Action

                        N
                             CH3                      N
                                                            N
                             N(CH 3)2
                                                                N
                                                                 CH3
                 Trimipramine (Surmontil)
                                                    Mirtazapine (Remeron)




            Cl
                                                N      Cl                             O
                        N      N            N
                                                N                N     N         N        N     OPh
                                        O                                         N
                                                                                          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.
                                                                                                                     31
                                                                            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




                                                                                                         32
                                                                Davis MDCH 5210 - CNS Stimulants, 2006
Mechanisms of Antidepressants:                             Mechanisms of Antidepressants:

                                                           NA & DA RI (NDRI)

                      Tryptophan              Tryptophan
                                                           Serotonin/NA RI (SNRI)
            5-HT1A                      LNAA
                            TPH                            5HT2A antagonist, NA & 5HT RI (SARI).
                       5-HTP                               2 antagonist, NA & 5HT RI
                           AADC
  Pre-synaptic
                       5-HT                       5-HIAA


                                        MAO

                                 5-HT
                                                5-HT1B


                              SERT



                  5-HT1A         5-HT2c
      5-HT2A                                   5-HT1B
                     Post-synaptic

                                                                                                          33
                                                                 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.

                                                                                               34
                                                      Davis MDCH 5210 - CNS Stimulants, 2006

				
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