Antidepressant Medchem Flashcards
What do these acronyms represent?
DAT
NAT
SERT
DAT – dopamine transporter
NAT – norepinephrine transporter
SERT – serotonin transporter
What is your understanding of these prefixes?
Des
Nor
Des- or Nor-: removal or loss of methyl group
What are the antidepressant Mechanisms of Action?
↑ NT activity by blocking their reuptake
↑ NT activity by blocking their metabolism
5HT & α2-Adrenergic Receptor Antagonists
Antidepressants - Drug selection is based on:
- Antidepressants - Drug selection is based on ADMET properties and side effect profile à altering patient’s brain chemistry
- 1st Generation – useful in certain instances
- Tricyclic Antidepressants (TCAs)
- Monoamine oxidase Inhibitors (MAOIs)
- 2nd Generation – less side affects
- Selective Serotonin Reuptake Inhibitors (SSRIs)
- Serotonin/Norepi. Reuptake Inhibitors (SNRIs)
- Atypical Antidepressants
- Dopamine & Norepi. Reuptake Inhibitors (DNRIs)
- 5HT-2 Antagonists/5HT Reuptake Inhibitors (SRMs)
- 1st Generation – useful in certain instances
Antidepressant MOA
- Mechanism of Action - Monoamine deficiency à we need to increase the level of MoA in the synapse - Block deactivation
- ↑ NT activity by blocking their reuptake
- ↑ NT activity by blocking their metabolism
- 5HT & α2-Adrenergic Receptor Antagonists
Tricyclic Antidepressants (TCAs) SAR
- Structure: Three cyclic structures that are fused and attached to an amine at some point.
- Structure of rings must be 6, 7, 6 or 6, 6, 6 for conformational restriction.
- Secondary amine TCAs are bound to two other carbons.
- If Alkene present on side chain, then possibility of cis-trans isomerism to occur which will impact SERT selectivity.
Tertiary amine TCAs
Imipramine (Tofranil)
Amitriptyline (Elavil)
Doxepin (Adapin, Sinequan)
Clomipramine (Anafranil)
Tertiary amine TCAs Characteristics
- Characteristics
- Lipophilic (can cross into the CNS) & low bioavailability (due to 1st pass metabolism)
- Inhibit NET (to a lower extent) and SERT (mostly)
- –OH & nor- or des-methyl active metabolites
- Many side effects – promiscuous receptor affinities
- Broad activity – can bind to histamine receptors (sedation), cholinergic receptors (antagonist – Anti-SLUDE), dopamine receptors (anti-dopaminergic effects), Na+ channels (cardio toxic)
- Promiscuous pharmacology = more side effects + broad spectrum activity of these agents
- 3o TCAs - low bioavailabilities but long t1/2 (10- 30h)
- Whatever reaches systemic circulation stays there for a long period of time
- 2D6 & 3A4 for metabolism – metabolites have long t1/2
- 3oN TCAs are rapidly metabolized to secondary amine TCAs (↑ plasma concs. of 2oN TCAs)
- More NET than SERT inhibition
- Contraindicated with MAOIs? Essentially doing the same thing – may lead to too much NT in the synapse
- Are they still useful? Yes, when a patient has failed other treatment options.
Imipramine
- (Tofranil)-Tertiary amine
- A dibenzazepine isostere of phenothiazine
- Increased synaptic Norepi/5HT concentrations by inhibiting reuptake
- N-desmethyl metabolite turns overall activity in favor of NET
- Tertiary amine TCA’s = more SERT than NET (Imipramine)
- Secondary amine TCA’s = more NET than SERT (Desipramine)
- Comes from the discover of chlorpromazine (antipsychotic)
Amitriptyline
- (Elavil)-tertiary amine
- A dibenzocycloheptene – not cis or trans because of symmetry
- Sensitive to photo-oxidation (protect HCl solutions from light – should be kept in amber bottles – dibenzoprolidineamine)
- Polymorphisms with 2D6 metabolism
- Similar to binding profile to imipramine
- Amitriptyline = tertiary amine, Nortriptyline = secondary amine
Doxepin
- (Adapin, Sinequan)-tertiary amine
- O-introduces asymmetry (geometric isomers) – changes functional group to dibenzoxepine which retains the antidepressant activity, but now there are geometric isomers:
- E (inhibits NET) 85%
- Z is the more active isomer and inhibits SERT 15%
- This preparation favors NET over SERT (85%/15%)
- Des or nor-methyl active metabolites can occur from tertiary amine
- O-introduces asymmetry (geometric isomers) – changes functional group to dibenzoxepine which retains the antidepressant activity, but now there are geometric isomers:
Clomipramine
- (Anafranil)- tertiary amine
- last major TCA introduced and most powerful
- A 3-Cl derivative of Imipramine, is 50X more potent
- Exhibits 50% PO bioavailability
- Metabolized by 2D6 (variable metabolism depending on patient phenotype)
- Active metabolite is inhibiting NET > Clomipramine
Secondary Amines TCA’s
Desipramine and Nortriptyline
Desipramine and Nortriptyline
- Secondary Amines
- High bioavailabilities & lipophilic (CNS & breast milk)
- More NET than SERT inhibition
- 1A2 (N-demethylation to 1o amines) & 2D6 (2-OH)
- Extra Info: Carry the same features of the tertiary amine, but side effects are slightly lower. Desipramine comes from imipramine. Nortriptyline comes from amitriptyline. Both undergo a loss of methyl group. Primary amines have a dramatic loss of antidepressant activity. Aromatic hydroxylation occurs at C2 (prepares for further metabolism)
Mono Amine Oxidase Inhibitors (MAOIs)
Isocarboxazid (Marplan)
Phenelzine (Nardil)
+/- Tranylcypromine (Parnate)
Selegiline (Elderpryl, Emsam Patch)
Mono Amine Oxidase Inhibitors (MAOIs) General Characteristics
- Irreversible treatment agents
- Have a long duration of action (tie up the enzyme)
- Undergoes oxidative deamination
- Two Isoforms (MAO-A & MAO-B)
- MAO-A: selectively deaminates 5-HT, melatonin, Epi. & Norepi.
- MAO-B: 75% of brain MAOs, deaminates phenethylamines (DA, 5-HT)
- Four irreversible MAOIs (form covalent bonds with MAOs) - long acting despite their short half-life→longer washout period before switching patient to other medication
- ↑ conc. of NE & 5HT @ synapse by ↓ metabolism
- DDIs: (SSRIs, Amphetamines, Tyramine, etc.) – serotonin (5HT) syndrome, hypertensive crisis, etc.
- Most agents are non-selective
- Tyramine (found in cheese) can cause hypertensive crisis
Isocarboxazid
(Marplan)
A hydrazine MAOI
Non-selective irreversible MAOI = inhibits both MAOA and MAOB
Isoniazid (anti-TB agent) was the starting point
Phenelzine
(Nardil)
A hydrazine MAOI
Molecule that is rapidly absorbed, Elim. t1/2 = 1-4 h
Non-selective irreversible MAOI (“suicide” inhibitor)
MoA: free radical reactive species
Suicide inhibition – forming reactive species that stick around and inhibit the same enzymes
NAT polymorphisms exist – may need to adjust the dose for patients
+/- Tranylcypromine
(Parnate) - racemicA cyclopropyl amphetamine analog
Introducing isomerism
Non-selective irreversible MAOI
(+) - enantiomer is the eutomer
More rapid onset vs. Phenelzine
Competitive inhibitor of 2C19 and 2D6
Selegiline
(Elderpryl, Emsam Patch)
A propagylamine MAOI
Selective, irreversible, MAO-B inhibitor (lose selectivity @ higher doses)
L-Selegiline is the eutomer
Why a patch formulation?
Skip GI & liver MAO inhibition & avoid hypertensive crisis
Metabolism: 2B6/2C19 to L-Amphetamine (vasoactive)
Contains a chiral carbon à L-isomer is the more active
Allows patients to have a less restrictive diet – bypasses GI and liver
Selective Serotonin Reuptake Inhibitors (SSRIs) Characteristics
Most commonly prescribed (less SE vs. TCAs)
Well absorbed, longer acting, requires 2D6 & 3A4 for activation/deactivation
Side-effects experienced at higher doses (why?)
Most are arylalkylamine derivatives (mostly arylpropylamines, n = 3)
(±)- Fluoxetine
- (Prozac)
- Phenoxyphenylalkylamine
- S- (-)-isomer (SERT selective) & R- (+)- is longer acting
- SERT inhibition depends on phenoxy ring substitution
- EWGs in 4th position ↑SERT inhibition
- 2,4- or 3,4-disubstitutions ↓ selectivity
- Equally active metabolite is S-Norfluoxetine = longer acting
- Fluoxetine & Norfluoxetine - potently inhibit 2D6 & 3A4
- In racemic form, fluoxetine benefits from a balance of S and R isomers (selectivity and duration of action)
- 2D6 may appear as a poor metabolizer due to potent inhibition of 2D6
- Norfluoxetine is also known as des/nor-methyl fluoxetine
Paroxetine
- (Paxil)
- A phenoxyphenylalkylamine constrained analog of Fluoxetine
- 50% PO bioavailability due to first pass metabolism
- 3S,4R- (-)-isomer is marketed as paroxetine
- At low dose, deactivates 2D6 via reactive metabo. & ↑ plasma conc. of paroxetine
- O-quinoid reactive metabolite leads to deactivation of 2D6 = mechanism-based inhibition of 2D6
- May need to find an alternative if this is occurring at low doses
(±)-Citalopram
(Celexa) – Not on exam
A phenoxyphenylalkylamine derivative
80% PO bioavailability = undergoes minimal first pass metabolism
S- (+)-isomer (Escitalopram) is active
R- (-)-isomer (Inactive) clears more slowly (admin. S-isomer only)
Metabolized equally by 2C19 (37%), 2D6 (28%) & 3A4 (35%)
If 2D6 is inhibited, there is still a way for the drug to be metabolized
N-Desmethylcitalopram – maj. metabolite (an active SSRI)
R-isomer does not have much activity and clears more slowly
Citalopram → escitalopram via resolution of isomers, not via metabolism
You arrive at the same active metabolite whether you start with citalopram or escitalopram
Sertraline
(Zoloft) – Not on exam
A phenylalkylamine & very selective SSRI
S, S- (+)-diastereomer is the eutomer
20-36% oral bioavailability………..
Metabolized to N-Desmethylsertraline (10X< active)
Minimal 3A4, 2D6 related DDIs. Why?
Contains 2 chiral centers
2B6 is the major metabolizing enzyme, the others play a minor role in metabolism
Fluvoxamine
(Luvox):
An Oxime ether
C=N (imine) bond confers geometric isomerism (E/Z)
E-isomer is active
C=N is susceptible to photo-isomerization by UV-B (290-320 nm) to inactive Z-isomer
50% bioavailability (1st pass metabo.)
The Z-isomer is inactive and can be brought about by exposure to light
Venlafaxine
(Effexor):
A methoxyphenethylamine
30X > potent inhibitor of SERT vs. NET
15% PO bioavailable due to first pass metabolism
↑ Daily dose - sequential inhibition of both SERT & NET
ODV or O-Desmethylvenlafaxine (80% PO bioavailable)-new drug
Minimally impacted by first pass metabolism
Duloxetine
(Cymbalta):
5X > potent than Venlafaxine
S-isomer is more active
Low affinity for other receptors – fewer side effects à targets mostly 5-HT and NE
Derivative of fluoxetine – removed benzene and replaced with thiophene
In smoking, there is induction of 1A2 à rapid deactivation of duloxetine
Hydroxylation prepares the molecule for second-phase metabolism
Levomilnacipran
(Fetzima – approved for MDD in 2013):
NET/SERT inhibitor – Potentiates Norepi & 5HT (makes them more active)
Widely distributed/low (22%) plasma protein binding – important with NTI drugs that are highly protein bound
N-desethyl & p-OH metabolites are active (3A4’s role)
Milnacipran – (+/-)
Levomilnacipram is a “relative” of milnacipran
Bupropion
(Wellbutrin, Zyban) – atypical- Not on test
Better SE profile than TCAs
No CNS stimulant effects
t-butyl prevents N-dealkylation to amphitamine-like metabolites
Extensively metabolized – metabolites contribute to long duration of action
Trazodone
- Serotonin Receptor Modulators (SRMs)
- Structure: Arylpiperizine
- Desyrel)
- 5HT antagonist & Reuptake Inhibitor
- Rapidly absorbed (65% PO bioavailability)
- Chronic use ↓ post synaptic 5HT binding sites
- Hepatotoxic (idiosyncratic – not well explained)
- Dual acting – inhibiting 5-HT and inhibiting reuptake
- 3A4 is involved in metabolism. See below left.
- Metabolism leads to several active and reactive metabolites (iminoquinone and epoxide) that can lead to hepatotoxicity
- If the patient is GST compromised, it can lead to hepatotoxicity
Nefazodone
(Serzone??)
Serotonin Receptor Modulators (SRMs)
Structure: Arylpiperizine
Inhibits 5-HT2 & SERT
Sig. 1st pass effect - 20% bioavailability
Metabolized by & inhibits 3A4 (metabolites also inhibit 3A4)
Hepatotoxic: Inhibition of Bile Acid transport in the liver or Reactive Species formation via metabolism (3A4 → Quinone-imine species) – see above right
Vilazodone
(Viibryd)
Serotonin Receptor Modulators (SRMs)
Structure: Arylpiperizine
5-HT1A partial agonist & SERT inhibitor (SPARI)
50-72% bioavailable
>96% protein bound à do not administer with NTI drugs that are also highly protein bound
Extensive metabolism
Mirtazapine
SRM & BenazepineMirtazapine (Remron, Avanza, Zispin)
Classification: SRM & Dibenazepine
Inhibits presynaptic α2 & antagonizes 5HT2/3
A more potent isostere of Mianserin
Converted benzene into pyridine
Pyridine ring ↑ polarity & ↓ basicity
Brintellix
Multi-modalBrintellix (Vortioxetine - Approved for MDD in 2013)
Multi-modal: 5-HT1D,3,7 antagonist, 5-HT1B partial agonist, 5-HT1A agonist & potent SERT inhibitor (Ki=1.6 nM)
T1/2 = 66 h – longer acting, may promote compliance
Metabolism: 2D6 (maj.)
2D6 PM have 2X the plasma levels of Brintellix
Multi-target – hitting more than one beneficial target
Ki value – smaller the number = higher affinity
Others Antidepressant Therapies:
- Electroconvulsive therapy (ECT)
- Neuropeptides
- Substance P, Vasopressin, Galanin, etc.
- Herbals (St John’s Wart)
- Hyperforin
- Reuptake inhibitor of monoamines
- Inducer of CYP450
- Hyperforin
