Medicinal Chemistry 5210 - Fall 2006 - Davis Section.

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Medicinal Chemistry 5210 - Fall 2006 - Davis
Section.
http//www.pharmacy.utah.edu/medchem/faculty/davis
/mdch5210.html darrell.davis_at_hsc.utah.edu -
Office BPRB 295E - Phone [phone] Reading List
(Foyes 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.
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CNS StimulantsTherapeutic 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

• Block neurotransmitter reuptake (Most reuptake
  inhibitors affect either NE or 5HT)
• Tricyclic antidepressants Cocaine Selective
  Serotonin reuptake inhibitors
• 2. Promote Neurotransmitter Release Phenylethylam
  ines and related compounds. Amphetamine,
  Methylphenidate.
• 3. Block Metabolism - MAO inhibitors

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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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Xanthines (Caffeine, theophylline, theobromine)

• Mechanism(s) of action
• Inhibition of cAMP phosphodiesterase
• Competitive inhibitor of adenosine
• Promote NE release
• Promote intracellular Ca2 release

The order of potency for CNS activity is
Caffeine gt Theophylline gt Theobromine Theophylli
ne is an important drug for maintenance
treatment of asthma, but has some side effects
as you might expect.
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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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Amphetamine Structures
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Neuronal Synapse - NE Mechanism
Goodman and Gilman, 9th Edition
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Neuronal Synapse - 5HT
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Halogen Substituted Phenylethylamines.
The Halogen Rule Halogen substitutions
provide for 5HT selectivity/specificity. The
halogen rule, also applies to reuptake inhibitors.
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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. Dont quite
understand how you reduce food intake, without
diminishing hunger, but there you have it.
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Fen-Phen Lawsuits - Many
Ashcraft 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?
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Did Phen/Fen cause heart valve damage? Maybe -
Was there long term damage?
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. 20012862011-2014. ABSTRACT Con
text 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 Plt.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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The Good -old Days of Antidepressants
Dexamyl Dextroamphetamine amobarbital A
better one was Desbutal methamphetamine and
pentobarbital
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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 Parkinsons
disease. MAO inhibitors are sometimes used as
antidepressants, when patients dont 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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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)
dont 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.
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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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The pharmacology of putative early-onset
antidepressant strategies
Blier, P. Eur Neuropsychopharmacol. 2003
Mar13(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.
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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.
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Representative Tricyclic Structures. (The
important ones)
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IC-50s of 5-HT/NE/DA Reuptake Inhibitors
Lower IC50 means greater receptor affinity High
NE/5-HT - more selective for 5-HT
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Reuptake Inhibitor Structures
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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.
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Aldous Huxley Had the Answer
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Hallucinogen Structures
Mescaline 300 mg dose LSD 3000 MUs
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SAR for Phenylethylamine Hallucinogens, Stimulants
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Phenylisopropylamines
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Attention Deficit Hyperactive Disorder ADHD
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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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. 200667 Suppl 813-20. Candidate
gene studies of attention-deficit/hyperactivity
disorder
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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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Reuptake Inhibitors - Again
Can you see the SAR (structural)
similarity between fluoxetine, paroxetine,
sertraline,and atomoxetine?
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Newer Antidepressants Additional Mechanisms of
Action
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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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/Norepinep
  hrine reuptake inhibitor. Newer treatment for
  ADHD.
• Venlafaxine (Effexor) SNRI
• Bupropion (Wellbutrin) NDRI - Norepinephrine/Dopam
  ine

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Mechanisms of Antidepressants
Mechanisms of Antidepressants
NA DA RI (NDRI)
Serotonin/NA RI (SNRI)
5HT2A antagonist, NA 5HT RI (SARI).
?2 antagonist, NA 5HT RI
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Venlafaxine/Bupropion Structures
Bupropion (Wellbutrin) NDRI Norepinephrine/Dopamin
e
Venlafaxine (Effexor) SNRI
These are structurally unrelated to other
tricyclics and perhaps are Mechanistically
distinct.