1. Antidepressants Tricyclic antidepressants (TCAs)
Selective serotoninreuptake inhibitors (SSRIs)
Selective norepinephrine reuptake inhibitors (SNRIs)
Monoamine oxidase inhibitors (MAOIs)

2. TCA
TCAs Introduced in 1957 by isosteric replacement of phenothiazines’ “S” with a “C-C” isostere
This isosteric replacement also causes a change in the numbering system
Numbering begins at the first carbon next to the isosteric replacement
If there is a substituent on one of the rings, then start numbering on that ring
General structure

3. Consequence on Ring Geometry

4. This has several consequences with respect to ring angles
α is decreased, a β angle and γ angle is introduced causing the ring to twist
dramatic decrease in affinity for the dopamine receptor; most TCAs are no longer dopamine antagonists, while a few have weak dopamine antagonism
Increased affinity for the norepinephrine, serotonin presynaptic membrane transporter (Uptake-1)
TCA’s work by competitively inhibiting Uptake-1 for norepinephrine and serotonin
TCA’s are generally more selective for the norepinephrine transporter as compared to serotonin with the sole exception of clomipramine

5. SAR
Features common to all TCAs include: (1) A protonatable nitrogen, (2) Two aromatic rings and (3) Approximately a 2-carbon distance between the protonatable nitrogen and an aromatic ring
TCA Substitutions
Not much ring substitution seen with these drugs, unsubstituted phenyl rings are equal. Removal of a phenyl ring results in total loss of activity
Electron withdrawing groups are not important for activity as with the phenothiazines
Electron withdrawing groups can change selectivity from norepinephrine transporter to serotonin transporter and some substitutions can result in a loss of activity (Clomipramine)
The C10–C11 bridge can be an ethylene or vinyl with no change in activity. In fact the C10–C11 bridge is not required; breaking the ring at this point can retain activity (see SSRIs)

6. γ Nitrogen Substituents
Potency is in order: 3º > 2º > 1º amine
Although overall the TCAs are selective for the norepinephrine transporter (except clomipramine) the 3° amine is more selective for the serotonin transporter as compared to the corresponding 2° amine; and 2° amines are more selective for NE transporter
3° amines are more anticholinergic and antihistaminergic than 2° amines. In fact more bulk on the nitrogen follows the anticholinergic SAR
Ethyl or higher alkyl groups lead to a loss of activity and an increase in toxicities. Toxicity increases with increasing chain length
2o amines’ antidepressant activity followed by stimulation

7. Nomenclature of Tricyclic Ring System

8. TCA Classification Based on the middle ring, or ring B
Dibenzazepines: have a nitrogen at C5 (Imipramine, trimepramine, clomipramine, desipramine)
Dibenzepines: no heteroatoms (Amitriptyline, nortryptiline, protryptiline)
Other tricyclics: some have an O in the epine ring, or an O and an N, an N in the eleven position, or a 6 membered middle ring (Doxepine)

9. What angles are present here?
2. Based on the substitution of the aliphatic nitrogen
2o amines: differences as discussed before (Desipramine, nortryptiline, protryptiline)
3o amines: differences as discussed before (Imipramine, trimipramine, clomipramine, amitryptyline, doxepine)
Common TCA side effects include Adrenergic, Seretonergic, Anticholinergic, Antihistaminic, α Blocker, Quinidine-like effect
What angles are present here?

10. Introduction of Clomipramine in 1990 offered the psychiatrist the first drug effectively to treat obsessive-compulsive disorder (OCD) serious enough to interfere with social or occupational functions

11. Miscellaneous Tricyclic Compounds
Maprotiline: The ethyl bridge forms a fourth ring (tetracyclic) resulting in skewing of the phenyl rings similar to the TCA’s
Doxepine: dibenzoxepine an isostere of the TCA’s and all else is the same as the TC’s
Amoxapine: Related to dibenzoxazepine antipsychotic loxapine without para methyl group which has been used in depressed psychotics with some success. Has more dopamine antagonistsic activity than some of the other antidepressants. Loxapine, interestingly, has little to no antidepressant activity
Mirtazapine: a dibenzazepine but mechanistically is not related to the TCA’s at all. It is thought to be presynaptic a2 adrenergic receptor blocker that normally inhibit the release of the NE and 5-HT, thereby increasing active levels in the synapse. It also blocks post-synaptic 5-HT2 and 5-HT3 receptors—thereby enhance serotonergic neurotransmission while causing a low incidence of side effects

12. Name  
Brand  
NEUI 
SUI  
Anti-DA   
Anti-His   
amitriptyline
Elavil, Endep, Tryptanol, Trepiline
yes
desipramine
Norpramin, Pertofrane
imipramine
Tofranil
nortriptyline
Pamelor
protriptyline
Vivactil
trimipramine
Surmontil
amoxapine
Asendin, Asendis, Defanyl, Demolox, Moxadil
doxepin
Adapin, Sinequan
clomipramine
Anafranil

13. SSRIs and Other Antidepressants
SSRIs come from breaking the TCA ring structure that decreases bulk on the phenyl end
The decreased bulk probably explains why these are not antagonists at the receptors that TCAs tend to antagonize (acetylcholine, norepinephrine, histamine)
The group on the phenyl ring probably explains the selectivity for the serotonin transporter
Fluoxetine (Prozac) was the first SSRI type antidepressant introduced (1986). Other examples include venlafaxine and duloxetine , which are SNRIs.
Venlafaxine
Effexor®
Duloxetine
Cymbalta®
Serotonin-Norepinephrine Reuptake Inhibitors (SNRIs)

14. Citalopram and peroxetine are potent and most specific SSRIs primarily used to treat the symptoms of major depression, OCD, PTSD, panic disorder, GAD, and PMDD. Citalopram is sold as a racemic mixture, only the S-(+) enantiomer has the desired antidepressant effect. The S-(+) enantiomer is now sold as generic escitalopram. Citalopram metabolites desmethylcitalopram and didesmethylcitalopram are significantly less active (although sometimes considered as active metabolites).

15. SSRI Related Compounds
Atomoxetine and Reboxetine are selective norepinephrine reuptake inhibitors (SNRIs) which are very selective for inhibiting the norepinephrine reuptake transporter (Be careful, SNRI has also been used to stand for Serotonin Norepinephrine reuptake inhibitor such as venlafaxine)
These drugs lack a strong electron withdrawer on the phenyl ring that decreases selectivity for the serotonin transporter
They retain a similar side effect profile except adrenergic side effects (has more adrenergic side effects than SSRIs)
Atomoxetine is used in the US for ADHD and Reboxetine is used in Europe for depression
These drugs don’t have serotonergic side effects and, thus, decrease the risk for serotonin syndrome
Reboxetine
Vestra®
Atomoxetine
Strattera®

16. New Molecular Entity in 2009: Milnacipran
Basic, the cyclopropane ring is completely rigid and will dominate the 3-D structure of the drug
Racemic; however, the 'active' d-isomer having a longer half-life than the 'inactive' l-isomer. The approved drug is the Hydrochloride salt
SNRI in 3:1 ratio and used for the treatment of clinical depression (serotonin) and fibromyalgia (NE)
Well absorbed after oral dosing (bioavailability of 85%), meals do not have an influence on the rapidity and extent of absorption
Conjugated to the inactive glucuronide and excreted in the urine as unchanged drug and conjugate. Only traces of active metabolites are found. Enzymes of the CYP class do not play a role in the metabolism of Milnacipran so that the risk of interactions with drugs metabolized by CYP enzymes is minimal.

17. (discontinued due to liver toxicity)
Triazolopyridines contain a fused triazole ring and a pyridine ring, e.g., trazadone, which have a complex pharmacology
Nefazodone is an analog
The N closest to the triazole ring and the phenyl ring on the end opposite the triazolopyridine ring structure are the parts that interact with the receptor
These drugs are selective inhibitors of the serotonin transporter.
They are not considered to be SSRIs due to a different side effect profile
They are also good a blockers, and 5-HT2A antagonists
Nefazodone
Serzone®
(discontinued due to liver toxicity)

18. MAOIs
New antidepressant introduced but withdrawn due to liver toxicity, however, increased interest on hydrazines and hydrazides for antidepressants
Iproniazide
Antitubercular but CNS stimulant
Which later shown to be MAOI resulting in  NE & 5-HT
Isoniazide
Antitubercular but too polar
hydrazines
Thus MAOIs based on the hydrazine molecule have been extensively studied. Hydrazine, itself, has no MAOI activity
Must have a free amino at one end to be active; a protonatable terminal N is necessary; those without a terminal N are prodrugs and must be bioactivated
Must have at least one free hydrogen on each nitrogen
Adding an alkyl group to one nitrogen of hydrazine confers MAOI activity: Ethyl is the most potent of the series methyl, ethyl, propyl, etc. Branching with a methyl group does not affect potency

19. Ring Additions & Disubstiturions
Adding a phenyl ring produces a compound with no MAOI activity
Adding a benzyl ring confers good activity, adding a phenethyl (phenyl ethyl) ring is even more potent
More closely approximates norepinephrine, serotonin and dopamine, etc
Phenelzine
Disubstitution
N,N disubstitution on one end decreases, or loses, potency

20. Hydrazides & Mechanism
Hydrazides: hydrazine with one nitrogen forming an amide, e.g., Iproniazid and isocarboxazide
Isocarboxazide
Iproniazid
These drugs have lipophilic substituents that allow them to cross the BBB, where they are hydrolyzed to the active species. This increase the potency by allowing more drug to reach the site of action
Note isoniazide is a hydrazide but is not bioactivated
Mechanism of Action - MAOIs covalently bind MAO, irreversibly inhibiting the reaction.
An effective mechanism-based antidepressant agent. It is presumably oxidized to diazene (HN=NH) (which can then break up into molecular nitrogen, a hydrogen atom), and a phenethyl free radical that would be the active species in irreversible inhibition
Phenelzine

21. Competitive MAOIs
The present clinically useful irreversible MAOIs are mechanism-based as they form reactants that covalently bond the enzyme or its cofactor
Thus they may continue their action up to 2 weeks after administration is discontinued
The harmala alkaloid harmaline and harmine are competitive inhibitors of MAO and are CNS stimulants
Moclobemide has received considerable attention. It is an effective antidepressant without producing hypotensive crisis which is a reversible inhibitor of MAO-A and permits metabolism of dietary tyramine, however, caution is still needed to avoid excessive intake (of cheddar cheese, feva beans)

22. Miscellaneous MAOIs (-)-Selegiline
Tranylcypromine
The distance from the phenyl to the amine is closer to norepinephrine
The cyclopropyl group is very strained (reactive) and alkylates the enzyme
The trans isomer is more potent than the cis isomer
The ring is more unstable and binds the enzyme better
(-)-Selegiline
Has an acetylene functional group that is unstable
Results in covalent bond to the enzyme
Part of its metabolic fate is N-dealkylation to methamphetamine
Selegiline is the (–) isomer and so it forms (–) methamphetamine not the active (+) form as shown
Selective MAO-B irreversible inhibitor (at lower doses)

23. Study Guide
What is the consequences of ring geometry on activity with the isosteric replacement of S with -CH2CH2-
What are the common structural features of TCAs
What are the effect of ring substitution by an electron withdrawing group on TCAs?
Activity towards NE vs 5HT transporter system of 1o, 2o and 3o amines on the side chain.
Classes of TCAs based on both ring system and side chain amine with examples. Also know the angles present in each class of compounds.
Structures and activity of misc.: maprotiline, doxepine, amoxapine, mirtazapine.
What is SSRI and SNRI? How can you generalize from structures? How was SSRI developed from TCAs? Know all about milnacipram. Is trezadone an SSRI? Why or why not?
What are different classes of MAOIs? SAR of hydrazine derivatives. What are selective MAO-A and MAO-B inhibitors?