MED CHEM LEC 30-31

Structure of Serotonin

Structure of Norepinephrine

Structure of Epinephrine

Structure of Dopamine

Biogenic Amine Hypothesis

Depression is coincident with diminished NT of naturally occurring amine NT )dopamine, NE, and serotonin = monoamines)

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Binding of antidepressants to monoamine transporter occurs immediately, tho therapeutic effects take 3-6 weeks, and chronic administration is necessary, suggesting physiological changes are necessary.

Receptor Sensitivity Hypothesis

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1. There is an increased sensitivity and number of postsynaptic NE and serotonin receptors that lead to depression


1. Hypersensitive receptors keep NE and serotonin levels low → signals to upregulate the number of neuronal receptors
2. Receptor down-regulation and desensitization take → Consistent with observed delayed onset of drug effect
3. Through a study, it was found that increased NE and/or serotonin concentrations did not desensitize the postsynaptic receptors

The Permissive Hypothesis

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1. Emphasize the balance between serotonin and NE is critical to regulate mood - not just their absolute concentraitons or their receptors
2. If serotonin elvels are too low:


1. NE levels are unchecked by serotonin and NE concentrations can go too **high→** leads to mania
2. NE levels are unchecked by serotonin and NE cocnentrations can get too **low→** leads to depression
3. Agents affecting dopamine levels are also effective and neuropeptides might also be involved

What are the generally complications of DDI in terms of how the metabolism of a theoretical drug is altered and what the effect of that might be?

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1. Appropriate choice of drug depends on many factors


1. Other medications the patient is on (including herbal/supplements)
2. Diet
3. Genetic variance
4. non-responsiveness to a particular therapy
5. Other disease
6. Tolerable SE/compliance
7. Routes of metabolism for chosen drug
2. If another drug (drug B) you are taking is able to inhibit the enzymes, there can be a buildup of drug A which can lead to toxic concentration

Which cytochrome P450 enzymes are most often involved with drug metabolism and how does the number of CYPs involved translate to the likelihood of drug-drug interactions?

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1. CYP3A4 and CYP2D6 are the most involved
2. If an antidepressant is metabolized by more than one CYP450 isoform in parallel, genetic variance or drug interacts are less likely to be an issue due to CYP isoform inhibition
3. If the drug is metabolized by one CYP450 isoform, the potential for DDI increases

Know how P-glycoproteins affect drug concentrations in various areas of the body and how this relates to the effect a drug has

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1. P-glycoprotein transporters are membrane transport protein responsible for effux of many drugs
2. They are expressed in the liver, pancreas, kidney, colon, and brain capillary endothelial cells and placenta
3. Limits penetration/retneion of drugs into thse compartments which modulates durg effectiveness nad localized toxicity (CNS)
4. Inhibition of Pgp can significantly increase drug concentrations in the CNS = leads to toxicity
5. Inhibition of Pgp can significantly increase drug concentrations in intestinal cells = increased bioavailbility
6. Ex: grapefruit


1. Compounds within the fruit can inhibit CYP3A4 and Pgp to increases drug concentration

What monoamines do monoamine oxidase inhibitors metabolize and how? In other words, what intermediates and metabolites do MAO enzymes generate from serotonin? 

From serotonin, MAO can convert it into 5-HIAL

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ALDH can then convert it into 5-HAA

Know how monoamine oxidase inhibitors are used to treat depression.

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1. Serotonin, melatonin, noradrenaline, adrenaline → mainly broken down by MAO-A
2. Phenethylamine and benzylamine are mainly broken down by MAO B
3. Both forms can break down dopamine, tyramine, and tryptamine equally
4. By inhibiting MAOs, we increase concentrations of these monoamines (cause not breaking them down)

Two subtypes of MAO

* MAO A
* MAO B

Name the 1st generation MAOIs

* Pargyline
* Tranylcypromine/Parnate
* Isocarboxazid/Marplan
* Phenelzine/Nardil

First gen MAOIs are irreversible/reversible?

Irreversible - they bind covalently to the MAO enzymes (usually with the flavin int he active site)

First gen MAOIs are selective/non-selective?

Nonselective - binds covalently to both MAO-A and MAO-B (all future a reactive functional group

Name hte 2nd gen MAOIs

* chlorgyline
* deprenyl/selegiline

2nd gen MAOIs are irreversible/reversible?

Irreversible

2nd gen MAOIs are selective/non-selective?

Selective (\* think because they are irreversible, they don’t want to bind onto an MAO until they know its the right one because they can come off later)

What is the mechanism of action of irreversible MAOIs and what distinct reactive functional groups do they have?

Selegiline/Deprenyl

* 2nd gen MAOI
* irreversible
* MAO-B selective
* early stages of Parkinsons disease - reduces symptoms (therefore) affecting dopaminergic neurons
* transdermal patch (Esam) is used to treat depression

Recognize the advantages of using a reversible, selective MAOI such as moclobemide over non-selective and/or irreversible MAOIs.

3rd gen MAOIs are irreversible/reversible?

reversible - binds non-covalently to the MAO enzymes

3rd gen MAOIs are selective/non-selective?

selective

Moclobemide/ clobemix

* 3rd gen MAOI
* Reversible
* MAO-A selective
* not approved in the US
* shorter duration of action than other MAOIs
* It is claimed that no significant rise in BP occurs when combined with amine such as tyramine- containing foods but patients are warned to avoid large amounts of tyramine containing foods

Side effects of MAOIs, the mechanisms by which these occur, and when MAOIs are contraindicated with other drugs.

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1. Hypertensive crisis (tyramine pressor response)


1. Inhibitor of MAO-A and MAO-B in the liver and GI leads to dietary tyramine accumulation and displacement of NE from neuronal storage vesicles
2. Hypertensive crisis - Cheese reactions!
3. A paid and severe rise in BP
2. DDI - drug A affects the metabolism and therefore circulating concentration of drug B


1. Serotonin syndrome (CNS toxicity) - acute, potentially fatal when co-administered with TCAs
2. Effects of too much serotonin present at the receptor: mild symptoms: shivering, diarrhea; severe symptoms: muscle rigidity, fever, and seizures
3. TCAs block monoamine reuptake → increase serotonin
4. MAOIs block monoamine degradation → increased serotonin
3. Wight gain
4. Liver damage (hydrazines)
5. Longer term use leads to downregulation of adrenergic beta receptors → orthostatic hypotension

Name the secondary amines of the tricyclic amine antidepressants (TCAs) - SNRIs

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1. Desipramine/Norpramin
2. Nortriptyline/Pamelor

How do SNRIs affect NE vs serotonin levels

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1. They are more selective for inhibiting NE uptake over serotonin uptake
2. Reduced SE compared to tertiary amines

Desipramine/Norpramin

* Secondary amines - SNRIs
* The active metabolite of imipramine (N-demethylation)
* Tends to be less sedating than other TCAs and tends to produce fewer anticholinergic effects

Nortriptyline/Pamelor

* Secondary amines - SNRIs
* Active metabolite of amitryptyline (N-demethylation)

Reboxetine/edronax

* The first SNRI
* **Nontricylic SNRI** (-**xetine**)
* Used for treatment of major depressive disorders
* Available in many countries - FDA concluded it is not better than others
* Weak CYP3A4/CYP2D6 metabolism; moderate P-gp inhibitor
* Still being questioned about efficacy in humans through animal models show exceptional activity

Atomoxetine/Strattera

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1. Secondary amines - SNRIs
2. **Non-tricyclic SNRI (-xetine)**
3. Developed as an antidepressant but was not efficacious as a monotherapy in large studies
4. Prescribed for ADHD >6 yo
5. Can help some patients with combined depression and ADHD
6. >1 million prescriptions in the US alone in 2020

Imipramine

* tertiary amine TCA - NSRIs (NE and serotonin reuptake inhibitors)
* first TCA antidepressant to be developed
* serotonin inhibition> NE
* Demethylation to desipramine (SNRI) gives net results of non-selectivity

Amitriptyline

* Tertiary amine TCA - SNRIs (NE and Serotonin reuptake inhibitors)
* conformationally restricted
* (\*i-ma - trip over because I have no room- I am restricted)
* Equal affinity towards NE and serotonin (for uptake, not receptor binding)
* Sensitive to photo-oxidation (HCL solutions need to be protected from light to avoid ketone formation and precipitation)

Why are TCAs used less frequently compared to some of the newer antidepressant agents now available?

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1. Secondary TCA antidepressants were once first line therapy for depresison due to the range of depressive and CNS disorders that could be treated with them. 
2. Now, they are second line treatment because of narrow therapeutic window (efficacy to toxicity ratio) and ADE and the development of new drugs that are better tolerated andhave different/fewer ADE.

Venlafaxine/ Effexor

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1. Nontricyclic NSRIs
2. Preferential affinity for Serotonin reuptake (30x more potent for SERT over NET)
3. The increasing dose can inhibit both SERT (serotonin transporters and NET
4. Dose-dependent ADE profile
5. Key concern: prolonged QT interval (cardiotoxicity) at normal dose
6. Distributed in breast milk
7. Metabolized by CYP2D6 to Desvenlafaxine

Desvenlafaxine/ODV

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1. Nontricyclic NSRIs
2. Approved in US and Canada
3. 10 x more potent at 5- HT uptake inhibits over NE uptake
4. Most common side effects: is nausea
5. Metabolized by CYP3A4 ( N-demethylation) and O-glucuronidation

Duloxetine

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1. Nontricyclic NSRIs
2. One of the most prescribed medications
3. Depression, diabetic peripheral neuropathic pain, fibromyalgia, osteroarthritiis pain
4. Inhibits both SERT and NET (5-fold preference for SERT)
5. Low affinity for other neuroreceptors → low incidence of ADE

Understand how SSRIs are proposed to work and that they are the most widely prescribed antidepressants and why.

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1. Working hypothesis on the SSRI MOA


1. SSRIs block the 5-HT transporter so 5-HT is not reabsorbed 


1. Increases the concentration of 5-HT in the synaptic cleft
2. Excess 5-HT overstimulates the post-synaptic receptors
2. After \~2 weeks, pre-post synaptic receptors are significantly down-regulated in CNS and the number of 5-HT transporters is reduced
3. Consistent with delayed onset of action of SSRIs
2. Selective for inhibiting 5-HT reuptake transporter 


1. Because of this selectivity and potency, inhibition of 80% of SERT leads to antidepressant effects

Know the general side effect profile of the SSRI class

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1. Compared to TCA, SSRIs cause more nausea, diarrhea, agitation, insomnia, sexual dysfunction, and anorexia
2. Compared to TCA, SSRIs cause less cardiotoxicity, dizziness, sweating, and blurred vision
3. Increased risk of suicide in children
4. Fatigue, anxiety, nausea, insomnia, sexual dysfunction
5. Potential to cause serotonin syndrome

Name SSRIs (3)

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1. Fluoxetine
2. Sertraline
3. Paroxetine
4. CItalopram
5. Escitalopram

Fluoxetine

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1. Chiral, but sold as racemate
2. Several P450-related DDI due to CYP2D6 metabolism inhibition
3. Extensively N-demethylation (long-lived, active metabolite)
4. Inhibits CYP2D6 isoform→ clinical drug interactions

Sertraline

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1. SSRI
2. Extensively N-demethylated (long-lived, active metabolite)
3. T ½ : Sertraline : 26 hr, desmethylsertraline : 66hrs
4. Inhibits CYP2D6 isoform→ clinical drug interactions

Paroxetine

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1. SSRI
2. Several studies have associated paroxetine with suicidal thinking and behavior in children and adolescents 


1. (\* paro = parrot = kids like parrots as pets)
3. Inhibits CYP2D6 isoform→ clinical drug interactions

Citalopram

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1. SSRIs
2. Racemix
3. Not approved in pediatric patients (black box warning)
4. Increased risk of suicide in children/adolescents
5. Dosage >40 mg once daily is no longer recommended due the to risk of QT interval prolongation
6. Maintenance dosage: 20-60 mg
7. Does not inhibits an major P450 enzymes

Escitalopram

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1. SSRI
2. S-enantiomer of citalopram
3. Modestly better tolerated
4. More costly than racemic citalopram


1. (\*adding extra letters to the work = cost more to add)
5. Example of a chiral switch or “evergreening” to extend patent life

Know what is meant by “evergreening” or a chiral switch 

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1. Ex: escitalopram
2. A method to extend patent life by switching to using another enantiomer of a racemic drug

Mirtazepine/Remeron

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1. NaSSA (alpha2-noradrengergic antagonist/selective serotonin antagonist)
2. Atypical antidepressant
3. Alpha 2- receptor antagonist → increases extracellular NE because usually alpha 2 -agonist suppresses release of NE)
4. Antagonizes 5-HT receptors (allowing the release of NE and DA in reward areas of brain)
5. Does not inhibit the reuptake of serotonin
6. Tetracyclic antidepressant
7. Racemic
8. No SSRI-like ADE
9. Binds at histamine h1 (sedative properties)
10. Unlike TCAs, shows no significant cardiovascular ADE
11. More rapid onset and long-term efficacy
12. Used as an adjunct therapy to SSRIs and SNRIs

Trazodone/Olepro/Desyrel

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1. SARI (serotonin- 2 antagonist/ reuptake inhibitor)
2. Anxiety and depression, insomnia
3. First atypical antideprssant
4. 5-HT recepotr antagonist, 5-HT reuptake inhibitor, particle agonist at 5-HT 1A receptors
5. Low anticholinergic activity and virturally devoid of cardiovascular arrhythmia effects
6. Idiosyncratic hepatotoxicity ( due to iminoquinone)
7. Grapefruit juice interaction (CYP3A4)

Vortioxetine/Brintellix 

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1. SARI (Serotonin 2- antagonist/reuptake inhibitor)
2. first-line treatment for major depressive disorder and what major neurotransmitter it is affecting
3. Serotonin reuptake inhibitor with several other activities, including 5-HT3 receptor antagonism and 5-HT1A receptor agonism

Bupropion/Wellbutrin/Zyban

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1. DNRI (dopamine and NE reuptake inhibitor)
2. Antidepressant and 2nd line smoking cessation aid
3. Atypical antidepressant
4. Potent DA reuptake inhibitor (weak 5-HT/NE uptake inhibition)
5. Induces release of DA and NE
6. Risk of seizure as a SE

Esketamine

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1. Non-competitive N-methyl-d-aspartate (NMDA) receptor antagonist
2. Most recently approved drug for depression
3. Ketanest - IV
4. Spravato - nasal spray for treatment-resistant depression
5. Must be administered in a clinical setting, patients must remain on site for at least two hours after administration


1. This is because, during drug trials, patients experience sedation, difficulty speaking, confusion, numbness, and feelings of dizziness
6. MOA: NMDA receptors are inhibited by esketamine, this prevents ca2+ flux that would otherwise limit glutamate release. Glutamate release into synapse. Glutamate signaling and cascade re-established receptor responsiveness and receptor distribution