Antidepressants Med Chem Flashcards by Cory Montez

Tricyclic Antidepressants (TCAs) can contain all of the following EXCEPT:

A. Three cyclic rings

B. Quaternary amine

C. Secondary amine

D. Tertiary amine

E. Double bond on carbon linker

B. Quatnary Amine

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Which of the following statements is true regarding TCAs?

A. Consist of 2 fused rings and an amine

B. Must consist of 3 aromatic rings

C. When TCAs are metabolized they are converted from secondary amine TCAs to Tertiary amine TCAs.

D. Must consist of 3 aromatic and non-aromatic rings.

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Which of the following options can be the carbon number for each ring in TCAs from left to right? (Select All)

A. 5,6,7

B. 6,6,6

C. 6,5,6

D. 6,7,6

E. 7,6,7

B. 6,6,6

D. 6,7,6

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In the picture provided, the structure on the left is a ___ TCA and the structure on the right is a ___ TCA

A. Primary, Secondary

B. Secondary, Primary

C. Tertiary, Secondary

D. Secondary, Tertiary

C. Tertiary, Secondary

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Which of the following statements regarding TCAs are true? (select all)

A. TCAs are highly lipophilic

B. Can distribute into breast milk

C. Secondary and Tertiary amines have similar bioavailabilities

D. Block NET only while leaving SERT unaffected

E. Block NET and SERT reuptake transporters

A. TCAs are highly lipophilic

B. Can distribute into breast milk

E. Block NET and SERT reuptake transporters

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___ amine TCAs have higher bioavailability than ___ amine TCAs.

A. Secondary, Tertiary

B. Tertiary, Secondary

A. Secondary, Tertiary

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The following picture shows the structure of the TCA Imipramine. What is the name of the core structure within this drug?

A. Dibenazl

B. Dibenzazepine

C. Dibenzalkyl

D. Dibenzyalkonium

B. Dibenzazepine

Di-Two

Benz- Benzne

Az-Nitrogen

DiBenzAzepine

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Tertiary TCAs will block both SERT and NET reuptake transporters equally but when they are converted to Secondary TCAs they will favor the blockade of ___ reuptake transporters.

A. SERT

B. NET

Secondary Amine TCAs will exhibit more NET reuptake blockade rather than SERT.

This includes a tertiary amine that has been converted to a secondary amine or a medication that is already a secondary amine.

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What type of reaction is occuring in the conversion of a Tertiary amine TCA to a Secondary amine TCA?

A. Demethylation

B. Hydroxylation

C. Esterification

D. None of the above

A. Demethylation

However, metabolites of TCAs can either be Des-methy (or nor-methyl) or OH (hydroxylated) metabolites.

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GO OVER SLIDE 7 and Isomerism

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What is the new group in the TCA amitriptyline called?

A. Dibenzazepine

B. Dibenzylalkonium

C. Dibenzocycloheptene

D. None of the above

C. Dibenzocycloheptene

Di= Two

Benzo= Benzene

Cyclo= Cyclic

Heptene= 7 carbons (double bond)

Dibenzocycloheptene

Do not get this group confused with the Dibenzazepine group in Imipramine. They look very similar, the only difference is the Nitrogen present in Imipramine.

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What enzyme is responsible for metabolizing a Tertiary amine TCA to a Secondary amine TCA?

A. CYP3A4

B. CYP2D6

C. CYP2E1

D. CYP1A2

B. CYP2D6

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In the TCA Doxepine, what is the name of the functional group circled?

A. Dibenzazepine

B. Dibenzocycloheptene

C. Dibenzoxepine

D. None of the above

C. Dibenzoxepine

Di- Two

Benz- Benzine

Ox- Oxygen

DiBenzOxepine

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The TCA Doxepine is available in E (Trans) and Z (CIP) conformations. Of the two isomers which is more active and inhibits both NET and SERT?

A. Z isomer

B. E isomer

A. Z isomer

It is available as a racemic mixture containing both E and Z. There is 85% E and 15% Z

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When comparing the structures of Amitriptyline and Doxepine what occurs with the structural addition of Oxygen to Doxepine?

A. Adds Lipophilicity

B. Decreases COMT metabolism

C. Increases dopaminergic reuptake

D. Introduces Isomerism

D. Introduces isomerism

By adding the oxygen the molecule can now assign priority across the double bond and can exist as the E or Z isomer.

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When comparing the structure of Imipramine and Clomipramine, what does the addition of the chloro group on carbon 3 cause? (Select All)

A. Increased Lipophilicity

B. Decreased Lipophilicity

C. Increases Potency

D. Increases Dopamine reuptake blockade

A. Increases lipophilicity

C. Increases Potency

It actually increases potency by more than 50x.

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What enzyme is responsible for converting Clomipramine to N-Desmethyl-Clomipramine (active)?

A. CYP3A4

B. CYP2D6

C. CYP2E1

D. CYP1A2

B. CYP2D6

Remember that when you go from a tertiary to a secondary TCA then CYP2D6 was utilized.

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When looking at this picture provided, what do you expect to be true if the patient took Clomipramine and is also a Poor Metabolizer (PM) of CYP2D6? (select all)

A. Lower concentrations of Clomipramine

B. Higher concentrations of N-desmethyl-Clomipramine

C. Higher concentrations of Clomipramine

D. Lower concentrations of N-desmethyl-Clomipramine

C. Higher concentrations of Clomipramine

D. Lower concentrations of N-desmethyl-Clomipramine

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When Clomipramine is metabolized to N-Desmethyl-Chlomipramine it is expected to have ___ NET activity than the parent drug Clomipramine.

A. Less

B. More

B. More

This is because it is going from a tertiary to a secondary amine and secondary amines have more NET activity than tertiary amines.

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The following is the SAR of TCAs. In the picture provided, what is true regarding the blue carbon linker on the lower portion of the molecule? (Select All)

A. Must consist of 2 carbons

B. Must consist of Alkane or Alkene group

C. Must consist of 3 carbons

D. Can contain Alkyne groups

E. Can contain a double bond

B. Must consist of Alkane or Alkene group

C. Must consist of 3 carbons

E. Can contain a double bond

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The following is the SAR of TCAs. What is true regarding the third carbon circled in red?

A. Hydroxyl groups increase potency

B. Electron Withdrawing Groups (EWGs) increase SERT selectivity

C. Electron Withdrawing Groups (EWGs) increase NET selectivity

D. Hydroxyl groups increase SERT and NET selectivity

B. Electron Withdrawing Groups (EWGs) increase SERT selectivity

Short Answer: What does the term “Promiscuous Pharmacology” mean regarding the use of TCAs?

Promiscuous pharmacology essentially means indiscriminant pharmacology. In other words it binds to multiple receptor types such as:

Adrenergic receptors
Histamine receptors
Cholinergic receptors
Na Chennel-blocking effects

This is why TCAs can show a multitude of side effects.

In comprison to secondary amine TCAs, tertiary amine TCAs exhibit ___ bioavailability but ___ half-lives

A. Lower, Shorter

B. Higher, Shorter

C. Lower, Longer

D. Higher, Longer

C. Lower, Longer

The reason for this is because the parent drug that is a tertiary amine is already active and has its own effects. However, when it is metabolized it forms a secondary amine metabolite that is also active and exhibits its own effects as well.

When looking at the metabolism of Desipramine and Nortriptyline they will undergo ___ using the enzyme ___.

A. Methylation, 1A2

B. Methylation, 2D6

C. Demethylation, 2D6

D. Demethylation, 1A2

D. Demethylation, 1A2

Desipramine and Nortriptyline are already secondary amines (hence the des and nor in their drug name). As a result they only have one more methyl group to lose and they will lose that methyl group through demethylation just as tertiary amines will. However, the difference is secondary amines use the enzyme CYP1A2 rather than CYP2D6 to lose their last methyl group.

When the medication Desipramine or Nortriptyline is metabolized further, it is converted to a \_\_\_\_. from there it can be **hydroxylated** by use of the enzyme \_\_\_\_. A. Primary Amine, 2D6 B. Secondary Amine, 2D6 C. Tertiary Amine, 1A2 D. Primary Amine, 1A2

A. Primary Amine, 2D6 Since Nortriptyline and Desipramine are already secondary amines they will lose their last methyl group using CYP1A2 and become primary amines (no carbons attached). When they undergoes hydroxylation however they use the enzyme **2D6** again to put the hydroxyl group on the benzene ring at the **C2** position circled in purple.

What is true regarding the contrast between MAOIs and TCAs? A. MAOIs and TCAs both block the reuptake channels NET and SERT B. MAOIs and TCAs block only the reuptake channels of NET and SERT C. TCAs block reuptake channels NET and SERT but MAOIs block the metabolism of numerous monoamines. D. MAOIs specifically block the reuptake channels of numerous monoamines but TCAs block specifically NET and SERT reuptake channels.

C. TCAs block the reuptake channels NET and SERT but MAOIs block the metabolism of numerous monoamines.

Which of the following statments regarding MOAIs is false? A. Prevents metabolization of monoamines to aldehydes B. Blocks metabolism of Serotonin and Norepinephrine only C. Does not block reuptake channels of monoamines D. Prevents deactivation of monoamines E. Blocks MOA-A and MOA-B

B. Blocks metabolism of Serotonin and Norepinephrine only

In the picture provided what are the circled amine functional gorups converted to when MAO metabolizes them? A. Ketone B. Aldehyde C. Carboxylic D. Ester

B. Aldehyde

All of the following Neurotransmitters are metabolized by MAO EXCEPT: A. Epi & Norepi B. Serotonin C. GABA D. Dopamine E. Phenethylamine (PEA) F. Tyramine

C. GABA

In the MAOI Isocarboxazid what is the name of the functional group circled? A. Dibenzazepine B. Dibenzocycloheptene C. Hydrazine D. Dibenzoxepine

C. Hydrazine

What type of bonds do MAOI form with MAO-A and MAO-B enzymes? A. Ionic, reversible B. Ionic, irreversible C. Covalent, irreversible D. Covalent, reversible

C. Covalent, irreversible

Short Answer: MAOIs have short half-lives but are still very long lasting. Why is this?

MAOIs may have short half-lives but they form **irreversible covalent bonds** that permanently attach to MAO-A or MAO-B. THis essentially kills the enzyme in what is known as **Suicide Inhibition**. In order for the body to get MAO-A or MAO-B activity back it must synthesize them again. This process takes time so this is why it has a long lasting effect despite the shorter half-life ## Footnote **Also look at slide 15 to understand the free radical species**

The medication **Tranylcypromine (Parnate)** is an MAOI that is known as a ___ analog. A. Cyclopentyl B. Cyclopropyl C. Cyclobutyl D. Nitrobenzyl

B. Cyclopropyl

In the metabolism of the MAOI Tranlcypromine (Parnate) what do you expect to see if someone is an ultra metabolizer (UM) of NAT? (Select All) A. Higher levels of TCP B. Lower levels of N-Acetyl-TCP C. Lower levels of TCP D. Higher levels of N-Acetyl-TCP

C. Lower levels of TCP D. Higher levels of N-Acetyl-TCP Also know that Tranylcypromine inhibits 2C19 and 2D6

In the MAOI Selegiline, what is the name of the boxed functional group? A. Cyclopropyl B. Propagylamine C. Nitrocarbyline D. Nitropropyline

B. Propagylamine

What are the main differences between the MAOI Selegiline (Elderpryl) and other MAOI's such as Tranylcypromine (Parnate) and Phenelzine (Nardil). (Select All) A. Parnate and Nardil are both irreversible and selective MAOIs. B. Selegiline (Elderpryl) is an irreversible and selective MAOI C. Parnate and Nardil are both irreversible and non-selective MAOIs D. Selegiline (Elderpryl) is a non-selective and irreversible MAOI while Parnate and Nardil are both selective MAOIs

B. Selegiline (Elderpryl) is an irreversible and selective MAOI C. Parnate and Nardil are both irreversible and non-selective MAOIs

The MAOI selegiline will inhibit MAO-B selectively at ___ doses but will lose selectivity when given at ___ doses. A. Lower, Higher B. Higher Lower

A. Lower, Higher Selegiline is known as an irreversible but Selective MAOI. It will selectivly bind to MAO-B when given at lower doses but at higher doses it loses selectivity and will bind and inhibit both MAO-A and MAO-B.

When looking at the metabolism of Selegiline, what enzyme is being used to convert Selegiline to its Methamphitamine metabolites? A. CYP2B6 B. CYP2D6 C. CYP2E1 D. CYP3A4

A. CYP2B6

(Short Answer) Judging by the metabolites of Selegiline why is it dangerous to have larger amounts of metabolites?

The metabolites that are formed are forms of **amphetimines** and those are stimulatory and vasoactive so it causes constriction of blood vessels. As a result it increases the risk of developing high blood pressure and increased risk of hypertensive crisis. This is why it is dangerous to have high levels of metabolits of Selegiline.

The function of MAOIs is to __ concentration of NE and 5HT at the synapse by __ metabolism. A. Increase, Decreaseing B. Decrease, Increasing

A. Increase, Decreasing

What is the functional group boxed in the medication fluoxetine? A. Phenoxyphenylalkylamine B. Dibenzocycloheptene C. Dibenzazepine D. None of the above

A. Phenoxyphenylalkylamine Phenoxy- Phenyl group + oxygen Phenyl- phenyl group Alkyl- alkane chain Amine- amine group

In the medication Fluoxetine (Prozac) the ___ isomer is more SERT selective and the __ isomer is longer acting A. R(+), S(-) B. S(-), R(+)

B. S(-), R(+)

Regarding the SAR of Fluoxetine which of the following statements is true? (Select All) A. Electron Withdrawing Groups on C4 increase SERT inhibition B. Adding a 2,4 or 3,4 disubstitution will increase selectivity of SERT C. The equally active metabolite of the parent drug Fluoxetine is R-Norfluoxetine D. The equally active metabolite of the parent drug Fluoxetine is the S-Norfluoxetine. E. Fluoxetine and it's active metabolite Norefluoxetine can potentially inhibit CYP2D6 and CYP3A4

A. Electron Withdrawing Groups on C4 increase SERT inhibition D. The equally active metabolite of the parent drug Fluoxetine is the S-Norfluoxetine. E. Fluoxetine and it's active metabolite Norefluoxetine can potentially inhibit CYP2D6 and CYP3A4

Paroxetine has a structural modification in it known as a: A. Piperazine B. Piperidine C. Cyclonitryl D. Cyclopropylamine

B. Piperidine The group on paroxetine is known as a piperidine and is known as the **Constrained analog** of Fluoxetine.

Short Answer: What is the issue with increasing the dosage of Paroxetine?

Paroxetine is metabolized by CYP2D6 but at the same time it also deactivates CYP2D6. This can lead to accumulation of the paroxetine and this problem only worsens when the dosage of the medication is increased. Also it is sold as the S isomer.

The SSRI Fluvoxamine (Luvox) contains a functional group circled in blue. What is the name of this functional group? A. Nitroxide B. Oxime-ether C. Amide D. Nitro

B. Oxime-Ether

What is the purpose of the C=N double bond in Fluvoxamine (Luvox)? (Select All) A. Introduces geometric Isomerism B. Allows the creation of an Active E-isomer and Inactive Z-isomer C. Makes the molecule susceptible to photo-isomerization to the inactive Z-isomer. D. Increases hydrophilicity of the molecule

A. Introduces geometric Isomerism B. Allows the creation of an Active E-isomer and Inactive Z-isomer C. Makes the molecule susceptible to photo-isomerization to the inactive Z-isomer. **Look at how the isomerism takes place on slide 23**

The SNRI Venlafaxine (Effexor) contains a functional group circled in red. What is the name of the functional group? A. Dibenzocycloheptene B. Dibenzazepine C. Oxime Ether D. Methoxyphenethylamine

D. Methoxyphenethylamine Methoxy- Methyl-oxygen (far left side) Phenethyl- Phenyl + Ethane Amine- Amine group **MethoxyPhenethylAmine**

The SNRI Venlafaxine has an active metabolite known as **O-Desmethylvenlafaxine (ODV)**. What was so beneficial about this metabolite? A. Available as an injection B. ODV has a higher bioavailability than the parent drug Venlafaxine. C. Selectivity increases with ODV as you increase venlafaxine's dose D. Available as topical agent

B. ODV has a higher bioavailability than the parent drug Venlafaxine. When they discovered the metabolite had these properties they isolated the metabolite and sold it as the drug. Also know that venlafaxine has poor oral bioavailability and it is a more potent inhibitor of SERT in comparison to NET