Davis MDCH 5210 - CNS Stimulants, 2006 1 [email protected] - Office: BPRB 295E.

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Davis MDCH 5210 - CNS Stimulants, 2006

http://www.pharmacy.utah.edu/medchem/faculty/davis/[email protected] - 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.

Medicinal Chemistry 5210 - Fall 2006 - Davis Section.

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1. Block neurotransmitter reuptake (Most reuptake inhibitors affect either NE or 5HT)

Tricyclic antidepressantsCocaineSelective Serotonin reuptake inhibitors

2. Promote Neurotransmitter ReleasePhenylethylamines and related compounds. Amphetamine,

Methylphenidate.

3. Block Metabolism - MAO inhibitors

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:

CNS StimulantsTherapeutic Treatment for: Depression, Narcolepsy, Obesity

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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.

Non-Therapeutic CNS stimulants(all seizure inducers)

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Mechanism(s) of action:•Inhibition of cAMP phosphodiesterase•Competitive inhibitor of adenosine•Promote NE release•Promote intracellular Ca+2 release

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

NN

N

O

O

CH3

CH3

CH3

N

NN

N

O

O

CH3

CH3

H

N

NN

N

O

O

CH3

CH3

HN

NN

N

NH2

H

Caffeine

Theophylline

TheobromineAdenine

Xanthines (Caffeine, theophylline, theobromine)

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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

•Enhance neurotransmitter release•Block NT reuptake•Have direct agonist effects•MAO inhibition

Phenylethylamines

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CH2

CH NH2

CH3

CH

C

OCH3

O

N

H

N

O

H3

C H

N

O

H3

C CH3

Amphetamine

Prototype phenylethylamine. The good, the bad,

and the ugly

Methylphenidate

(Ritalin)

Used for attention-deficit-hyperactive disorder

Usually in children

Phenmetrazine

(Preludin)

Anorectic

Phendimetrazine (Plegine)

Anorectic

Amphetamine Structures

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Goodman and Gilman, 9th Edition

Neuronal Synapse - NE Mechanism

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Post-synaptic

Pre-synaptic

SERT

TryptophanTryptophan

5-HTP

5-HT

5-HT

MAO

5-HIAA

TPH

AADC

LNAA5-HT1A

5-HT1A5-HT2A

5-HT2c

5-HT1B

5-HT1B

Neuronal Synapse - 5HT

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“The Halogen Rule ™”

Halogen substitutions provide for 5HT selectivity/specificity. The halogen rule, also applies to reuptake inhibitors.

CH2

CH NH2

Cl CH2

CH NH2

CH3

CH3

CH2

CH NH

CH3

CH3

F3

C

4-chlorophenylethylamine

(5HT selective)

Phentermine

(DA selective)

Fenfluramine

(5HT selective)

N

H

HONH

2

Halogen Substituted Phenylethylamines.

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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 diminishinghunger, but there you have it.

A few thoughts on Anorectics.

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Ashcraft & Gerel LLP

The Victims' Rights Law Firm

Washington, D.C. Maryland (Baltimore Landover Rockville)

Virginia

FEN-PHEN DIET DRUG LITIGATION - FREQUENTLY ASKED QUESTIONS

IntroductionWhat 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?

Fen-Phen Lawsuits - Many

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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.

ABSTRACTContext 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

Did Phen/Fen cause heart valve damage? Maybe - Was there long term

damage?

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Dexamyl: Dextroamphetamine + amobarbitalA better one was “Desbutal” : methamphetamine and pentobarbital

The Good -old Days of Antidepressants

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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.

Monamine Oxidase (MAO) Inhibitors

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MAO SARPrimary 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.

N

N

O

N

H

H

NH2

CH3

N

CH3

C

CH

Iproniazid

1st generation

Irreversible, non-selective

Tranylcypromine

(Parnate)

1st generation

Selegiline

(Eldepryl)

2nd Generation

Irreversible, MAO-B

MAO SAR

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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.

Tricyclic Antidepressants

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Blier, P. Eur Neuropsychopharmacol. 2003 Mar;13(2):57-66Abstract: 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.

The pharmacology of putative early-onset antidepressant strategies

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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.

Tricyclic Antidepressant SAR-

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N

CH2

CH2

CH2

N(CH3

)2

N

CH2

CH2

CH2

NHCH3

F3

C

O CH

CH2

CH2

NHCH3

O CH

CH2

CH2

NHCH3

H3

C O

N

CHCH2

N(CH3

)2

Br

N

CH2

CH2

CH2

N(CH3

)2

Cl

Imipramine (Tofranil)Desipramine (Pertrofrane)

Fluoxetine (Prosac)Nisoxetine

Zimeldine (Zelmid)Clomipramine (Anafranil)

Representative Tricyclic Structures. (The important ones)

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Zoloft

Paxil

Lower IC50 means greater receptor affinityHigh NE/5-HT - more selective for 5-HT

IC-50’s of 5-HT/NE/DA Reuptake Inhibitors

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C l

C l N H C H3

F

O

OO

H2

C

N H

( C H2

)4

O C H3

O ( C H2

)2

N H2

N

F3

C

C l

C H2

C H2

C H2

N ( C H3

)2

N

B r

C H C H2

N ( C H3

)2

N

OH3

C

C H2

C H2

N H C H3

C HO

C H2

C H2

N H C H3

C HO

F3

C

S e r t r a l i n e ( Z o l o f t )

P a r o x e t i n e ( P a x i l )F l u v o x a m i n e ( L u v o x )

C l o m i p r a m i n e ( A n a f r a n i l )Z i m e l d i n e ( Z e l m i d )

N i s o x e t i n eF l u o x e t i n e ( P r o s a c )

N

H

C H3

O

C H3

A t o m o x e t i n e ( S t r a t t e r a )

Reuptake Inhibitor

Structures

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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.

NH

NH2

NH

NH2

OHO

HO

Miscellaneous CNS Stimulants - Hallucinogens

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Aldous Huxley Had the Answer

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NH2

CH3

O

CH3

O

OCH3

Mescaline

(a phenylethylamine)

N

OH

H

N(CH3

)2

Psilocin

(31 Mescaline Units)

N

NH

CH3

O

CH3

H

Tetrahydroharmine

(An indole alkaloid)

Similar to Mescaline in potency

100 mg Hallucinogenic dose

NH

N

H

N

O

CH3

CH3

CH2

CH3

CH2

Lysergic Acid Diethylamide

LSD-25

100 μ g Hallucinogenic dose

Mescaline ~300 mg doseLSD ~3000 MUs

Hallucinogen Structures

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OH

CH3

NHCH3

O

CH3

NH2

O

O

CH3

NHCH3

OCH3

OCH3

CH3

NH2

CH3

NH2

Amphetamine

CathinoneEphedrine, pseudoephedrine

(S)

(O)(H)

(S)

(S)

DOMMDMA

H3C

SAR for Phenylethylamine Hallucinogens, Stimulants

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O

O

CH3

NHCH3

(O)

MDMA

Phenylisopropylamines

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CH2

CH NH2

CH3

CH

C

OCH3

O

N

H

Amphetamine

Dextroamphetamine (Adderall, Dexedrine)

Methylphenidate

(Ritalin)

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.

Attention Deficit Hyperactive Disorder – ADHD

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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

Dopamine Receptors and ADHD

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What does this mean? Methylphenidate (Ritalin) treatment is controversialDextroamphetamine (Adderall) treatment is probably more controversialClinical 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.

Do we understand what causes ADHD?

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C l

C l N H C H3

F

O

OO

H2

C

N H

( C H2

)4

O C H3

O ( C H2

)2

N H2

N

F3

C

C l

C H2

C H2

C H2

N ( C H3

)2

N

B r

C H C H2

N ( C H3

)2

N

OH3

C

C H2

C H2

N H C H3

C HO

C H2

C H2

N H C H3

C HO

F3

C

S e r t r a l i n e ( Z o l o f t )

P a r o x e t i n e ( P a x i l )F l u v o x a m i n e ( L u v o x )

C l o m i p r a m i n e ( A n a f r a n i l )Z i m e l d i n e ( Z e l m i d )

N i s o x e t i n eF l u o x e t i n e ( P r o s a c )

N

H

C H3

O

C H3

A t o m o x e t i n e ( S t r a t t e r a )

Can you see the SAR (structural) similaritybetween fluoxetine, paroxetine, sertraline,and atomoxetine?

Reuptake Inhibitors - Again

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N

N

N

C H3

M i r t a z a p i n e ( R e m e r o n )

N

N ( C H3

)2

C H3

T r i m i p r a m i n e ( S u r m o n t i l )

N N N

N

N

C l

N N N

N

N

C l

O

O P h

C H2

C H3

O

T r a z o d o n e ( D e s y r e l )

N e f a z o d o n e ( S e r z o n e )

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.

Newer Antidepressants – Additional Mechanisms of Action

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•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

Some of the New(er) Guys

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Post-synaptic

Pre-synaptic

SERT

TryptophanTryptophan

5-HTP

5-HT

5-HT

MAO

5-HIAA

TPH

AADC

LNAA5-HT1A

5-HT1A5-HT2A

5-HT2c

5-HT1B

5-HT1B

5HT2A antagonist, NA & 5HT RI (SARI).

Serotonin/NA RI (SNRI)

NA & DA RI (NDRI)

2 antagonist, NA & 5HT RI

Mechanisms of Antidepressants:Mechanisms of Antidepressants:

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Bupropion (Wellbutrin) NDRINorepinephrine/Dopamine

Venlafaxine (Effexor) SNRI

These are structurally unrelated to other tricyclics and perhaps areMechanistically distinct.

Venlafaxine/Bupropion Structures

Davis MDCH 5210 - CNS Stimulants, 2006 1 [email protected] - Office: BPRB 295E.

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