Depression MED CHEM

How do SSRIs treat depression?

Treat depression by specifically blocking the reabsorption of serotonin in the brain, boosting its levels to help improve mood and emotional stability.

What are examples of SSRIs?

- Fluoxetine

- Sertraline

- Citalopram

Describe the SAR of fluoxetine/SSRIs.

- Para CF3 is essential for all SSRIs.

- Methoxy group on aromatic provides SNRI activity.

- Secondary amine is essential

- Mehtyl group on secondary amine is essential, increasing length decreases activity.

Describe the SAR of citalopram.

- Cyano group is essential via enhancing SERT binding.

- 2 Methyl groups attached to aromatic at the top ability to bidn to SERT, decrease activity.

- Tertiary amine blocks binding at noreadrenaline receptor so increases selectivity to SERT.

- Fluorine not essential however increase lipophilicty so increased membrane permeability.

- S enantiomer is more active R enantiomer (escitalopram)

What are the binding sites for citalopram on SERT?

- Orthosteric site

- Allosteric site

Describe the orthosteric site of SERT.

- Binding site for natural ligand, Serotonin

- Citalopram can bind to this

Describe the allosteric site of SERT.

A second citalopram molecule binds to boost and prolong the effect of the one at the main (orthosteric) site.

Why does S enantiomer of citalopram more active than the R enantiomer?

The R enantiomer binds similarly to the allosteric site as escitalopram but binds much weaker to the orthosteric site, competing with escitalopram and reducing its efficacy—explaining why pure S-enantiomer escitalopram is more effective than racemic citalopram.

How do SNRIs treat depression?

Blocking the reuptake of both serotonin and norepinephrine, enhancing their levels in the brain to improve mood, energy, and focus.

Describe the SAR to NET.

- Dimethyl at the top increases selectivity to NET.

- Secondary amine increases NET selectivity.

- Cyano group decreases activity at NET.

Describe Duloxetine, dual inhibitors of SERT and NET.

- Derived from fluoxetine

- Only S-isomer used

Describe venlfaxine, dual inhibitors of SERT and NET.

- Derived from TCAs

- Resembles opened TCA

- S isomer is SERT selective

- R isomer is SNRI selective

How do tricyclic antidepressants treat depression?

Blocking the reuptake of serotonin and norepinephrine via blocking SERT and NET, increasing their levels in the brain to improve mood.

Describe the SAR of tricyclic antidepressants.

- 6-7-6 ring system is essential. Provides more conformational flexibility.

- If present, double bond at X must be cis.

- Halogen or cyano group gives selectivity to SERT.

- Branching at bottom chain reduces activity via reducing affinity to SERT and NET.

What are examples of TCAs?

- Amitriptyline

- Chlomipramine

- Nortriptyline

What are examples of monoamine oxidase inhibitors?

- Phenlzine

- Iproniazid