MedChem Zhang - Antidepressants

What are the biological causes of Depression?

An imbalance in the level of serotonin (5-HT), Dopamine (DA), and/or norepinephrine(NE) in the brain ——- typically lower than normal

• Depression is DEFICIENCY of NE and/or 5-HT at functionally important synapses in the brain

What is the general MOA of antidepressants?

They increase the level of one or more of these neurotransmitters (DA, NE, or 5HT)

• They typically INCREASE RECEPTORS on the post-synaptic Neuron!!

3 general types of Antidepressants

1. MAOIs

2. Neurotransmitter reuptake inhibitors

3. Neurotransmitter reuptake inhibitor/receptor agonists/antagonists

MAO converts what to what in the enzyme breakdown of neurotransmitters

it breaks down the amine in dopamine, serotonin, or Norepi into an ALDEHYDE —- which is then broken down into an alcohol and carboxylic acid ratio

What NTs are metabolized by MAO-A?

5HT (serotonin) and NE (norepinephrine)

What neurotransmitters are metabolized by both MAO-A and MOA-B subtypes?

DA, tyramine, tryptamine, octopamine

What helps reduce MAO degradation of neurotransmitters?

Increased steric bulk on the AMINE!

• Increased steric bulk impedes interaction of the substrate with MAO - reduced susceptivity of oxidative deamination

What were the first class of MAOIs

Hydrazides (R-NH-NH-CO-R’)

• MOA —- irreversibly inhibits MAO - mechanism inhibition (suicide inhibition)

• Example:

  • Iproniazid (withdrawn 1960 due to hepatitis)

  • Isoniazed (anti TB drug - prodrug/parent compound to iproniazid)

  • Phenelzine

  • Isocarboxazid

Second class of MAOIs

Cyclopropylamines

• Angle strain from tricyclic ring next to amine is what blocks MAO

• Non-selective and irreversible MAOIs

• More CNS stimulation than other MAOIs

• Example:

  • Tranylcypromine (parnate)

What are the problems and interactions with MAOIs?

Consuming tyramine-contianung food (cheese, dairy, etc) —— cause HYPERTENSIVE CRISIS

• must have a wash-out period

• can also cause serotonin syndrome

What were the SECOND GENERATION (not second class) of MAOIs?

RIMAS

• Reversible Inhibitors of Monoamine oxidase-A (RIMAs)

• Bind to MAO-A selectively and reversibly —- shorter and safer acting MAOIs

• Example

  • Moclobemide

  • Toloxatone

TCA’s MOA

Increase the level of neurotransmitters level

They block reuptake NE/5HT into presynaptic nerve terminals —— results in increased synaptic levels of NT’s

• work at SERT (serotonin transporter) and/or NET (Norepi transporter)

4 types of NT tranporters (control the uptake/flux of substances by cells)

1. Solute carrier (SLC)

2. Ion channels

3. Water channels

4. ATP-driven pumps

What type of transporters (directional wise) are the SERT and NET transporters?

Symporters (same direction)

Nomenclature of SLC transporters

SLC#An

# = family
A = subfamily

n = individual family member or isoform

SLC6A2 - NET

SLC6A3 - DAT

SLC6A4 - SERT

Scaffold of TCAs?

3 cyclic rings

• 6-7-6 — OR

• 6-6-6

TCA’s additional MOA

• block SERT and/or NET —— Typically non-selective

• TERTIARY AMINES ==== least selectivity for SERT/NET

• SECONDARY AMINES ==== favor NET

Prototype of the 6-7-6 tricyclic antidepressant class

Imipramine (tofranil)

• a type of benzazepine

• REMEBER HOW TO NAME THEM!! (lowest face and number if possible)

The other 6-7-6 TCAs aside form imipramine

Desipramine, Amitriptyline, Nortriptyline, Protriptyline

For 6-7-6 TCA Structure-activity relationship —- what is OPTIMAL for activity ???

unsubstituted benzene rings !!!!

AND NON-PLANAR ring scaffolding

• if you put an EWG (highly negative charged agent) at position three it INCREASES Antipsychotic activity and decreases antidepressant activity

Key points about the Ring Nitrogen atom SAR for TCAs

• can be replaced by Sp2 or Sp3 hybridized atom

• So double bond from Nitrogen to another carbon not needed for activity!

Key points about the terminal Nitrogen atom SAR for TCAs

secondary terminal amine is typically > tertiary amine

• about the same but better overall activity for secondary amine

Key points about the side chain (to the terminal amine from rings) SAR for TCAs

• 3 atoms chain is EFFECTIVE!!!

• Shortening to 2 carbons (instead of 3) keeps the antidepressant activity

• BUT branching off the chain causes decrease in antidepressants activity

6-7-6 TCAs three routes of metabolism

1. Aromatic Hydroxylation PARA to N (leads to glucoronide)

   1. 2 and 8 positions equivalent

2. N-Dealkylation to nor1 and nor2 metabolites (1 or 2 methyl groups removed)

3. Bridge/”benzylic” hydroxylation (middle ring attaches OH at top)

---

IF there is no Ring N (middle ring N) ——- then para hydroxylation is not important

• only #2 and #3 metabolism (N-dealkyl and bridge benzylic)

Introducing an Oxygen into the main middle ring of the TCA structure does what?

Introduces asymmetry and causes TWO ISOMERS

• E isomer is preferred/main

• Z isomer is however, more potent inhibitor of SERT/NET

What TCA is considered the overlap antidepressant?

Amoxapine (oxygen in middle ring AND chlorine EWG on right benzylic ring)

Points about the 6-6-6 TCA ring structure

• not as stable as 6-7-6 TCAs

• Their problem? ——- rapidly metabolized/oxidized into inactive planar scaffolds —- lack of antidepressant action

How can we prevent planarity and lack of antidepressants action on 6-6-6 TCAs and 6-7-6 TCAs?

Incorporate a bridge structure between rings —- JUST NO DOUBLE BOND!!!

SSRIs were found to be more selective after what?

Removal of the bridge from TCA structures that created more selectivity towards SERT and NET

Points about SSRI’s

• Act by blocking SERT

• Fluoxetine was first clinically introduced

• Selectivity is relative; HIGH DOSE will block NET ALSO

Fluoxetine isomers

• Potency === S > R

• Metabolism Speed ==== R > S

• No relationship between selectivity and potency of SSRIs

Points about Escitalopram

S-isomer of Citalopram

• fewer side effects, lower dose required

• Therapeutic effects are in the S isomer of citalopram (escitalopram)

TCAs vs SSRIs

• SSRIs = TCA’s

• SSRI’s less side effects

What drug class was created because of lack of efficacy on both SERT and NET together equally?

SNRIs

This SNRI has more SERT activity than NET activity

Venlafaxine

If a SSRI, SNRI, or TCA has low Ki nM —- what does it mean?

Its binding affinity is HIGH for a drug!! Binds better!

Which SNRI has the highest potency and inhibits the reuptake of 5-HT and NE the most?

Duloxetine > Milnacipran > Venlafaxine

What is the new models for newer generations of Antidepressants?

Neurodegeneration model of depression

Gene expression theory of depression

The ‘Blue Gene’ theory of depression

Newer generations of Antidepressants

Arylpiperazines

• Trazadone

• Nefazodone

• Vilazodone

Tetracyclic antidepressatns

• Mianserin

• Mirtazapine

Others:

• Bupropion (DAT and NET inhibitor)

• Auvelity

• Vortioxetine

• Ketamine

• Brexanolone

• Zuranolone (first postpartum depression pill!!!!)