Antidepressants
1. Tricyclic antidepressants (TCAs)
2. Selective serotoninreuptake inhibitors (SSRIs)
3. Selective norepinephrine reuptake inhibitors (SNRIs)
4. Monoamine oxidase inhibitors (MAOIs)
TCA
N
NR1
R2
AB
C
1
2
37
5
6
8
9
10 11
General structure
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
N
NCH3
CH3
H3C
CH3
N
N
S
Promazine Imipramine
Consequence on Ring Geometry
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
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)
γ Nitrogen Substituents
1. Potency is in order: 3º > 2º > 1º amine
2. 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. 3° amines are more anticholinergic and antihistaminergic than 2° amines. In fact more bulk on the nitrogen follows the anticholinergic SAR
4. Ethyl or higher alkyl groups lead to a loss of activity and an increase in toxicities. Toxicity increases with increasing chain length
5. 2o amines’ antidepressant activity followed by stimulation
Nomenclature of Tricyclic Ring System
N
H
1
1 H - Azepine
N
2
2 H - Azepine
H
H N
H
1
2
37
5
6
8
9
10 11
a
b
cd
e
f
10,11-Dihydro-5H-dibenzo-[b,f]azepine(as in imipramine)
O
Oxapine Cyclopheta-2,5-diene
2
6
1
1
2
3
75
68
9
2,3,6,7-Dibenzocyclohepta-2,6-diene(as in amitriptyline)
O
1
2
3
7
56
8
9
11
10
a
b
cd
e
f
Dibenz[b,e]oxepine 11[6H]ylidene(as in doxepine)
TCA Classification
NCH3
CH3
N
R
X
R X Name
H
CH3
H
H
H
Cl
Imipramine
Trimipramine
Clomipramine
NCH3
CH3
Amitryptiline
1. Based on the middle ring, or ring B
a) Dibenzazepines: have a nitrogen at C5 (Imipramine, trimepramine, clomipramine, desipramine)
b) Dibenzepines: no heteroatoms (Amitriptyline, nortryptiline, protryptiline)
c) 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)
CH3 CH3N
O
Doxepine
2. Based on the substitution of the aliphatic nitrogen
a) 2o amines: differences as discussed before (Desipramine, nortryptiline, protryptiline)
b) 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
NH
CH3
N
Desipramine
NH
CH3
Nortriptyline
NH
CH3
protriptyline
What angles are present here?
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
Miscellaneous Tricyclic Compounds
CH3
HN
H3C
CH3
N
O
Cl
NO
HN
N
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
CH3N
N
N
Mirtazapine: a dibenzazepine but mechanistically is not related to the TCA’s at all. It is thought to be presynaptic 2 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
Name Brand NEUI SUI Anti-DA Anti-His
amitriptyline Elavil, Endep,
Tryptanol, Trepiline
yes
desipramineNorpramin,
Pertofraneyes
imipramine Tofranil yes
nortriptyline Pamelor yes
protriptyline Vivactil yes
trimipramine Surmontil yes
amoxapine
Asendin, Asendis, Defanyl, Demolox, Moxadil
yes yes yes
doxepin Adapin, Sinequan yes yes
clomipramine Anafranil yes
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.
H3CO
N
CH3
CH3
OH
S CH3
HN
O
VenlafaxineEffexor®
DuloxetineCymbalta®
F3C OCHCH2CH2NHCH3
Fluoxetine
Serotonin-Norepinephrine Reuptake Inhibitors (SNRIs)
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).
O
O
O
F
NH
NC
O
NCH3
CH3
F
HBr NCH3
C
O CH3
F
N
O
O
HO
HOParoxetine(Antidepressant; SSRI) Citalopram Hydrobromide (Celexa)
(Antidepressant; SSRI)Escitalopram Oxalate (Lexapro)
(Antidepressant; SSRI).
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
CH3
HN
CH3
O
AtomoxetineStrattera® CH3
O
O
NH
O
ReboxetineVestra®
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.
New Molecular Entity in 2009: Milnacipran
NH2
O N CH3
CH3 MILNACIPRAN
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 blockers, and 5-HT2A antagonists
H3C
O Cl
N
NO
NN
N
NefazodoneSerzone®
(discontinued due to liver toxicity) Cl
N
NO
N
N
N
Trazadone
MAOIs O
NH2NH
N CH3
CH3HN
NH
O
N
IsoniazideAntitubercular but too polar
IproniazideAntitubercular but CNS stimulantWhich later shown to be MAOI
resulting in NE & 5-HT
New antidepressant introduced but withdrawn due to liver toxicity, however, increased interest on hydrazines and hydrazides for antidepressants
H2N NH2
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
hydrazines
Ring Additions & Disubstiturions
Ring Addition
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
Disubstitution
N,N disubstitution on one end decreases, or loses, potency
NH2
HN
Phenelzine
Hydrazides & Mechanism
CH3
N O
O
HN
NH
CH3
CH3HN
NH
O
N
Hydrazides: hydrazine with one nitrogen forming an amide, e.g., Iproniazid and isocarboxazide
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.
Isocarboxazide Iproniazid
NH2
HN
Phenelzine
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
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)
O N CH2CH2N
H
C
O
Moclobemide
Miscellaneous MAOIs
► 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)
CHC
CH3
CH3
N
CH3
NH
CH3
NH2
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?