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MedChem Final > Thatcher - SSRIs > Flashcards

Thatcher - SSRIs Flashcards

1
Q

Mocolbemide

A

MAO Inhibitor

  • Early Drug (1950s) used to treat depression
    • along with TCA’s, had adverse side effects / toxicity
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2
Q

Imipramine

A

TCA = Tricyclic Antidepressant

  • Early drug for depression (along with MAO’s)
  • Adverse Side Effects & Toxicity
    • Lack of target selectivity
      • Cholinergic / Adrenergic / Histaminergic receptors
        *
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3
Q

Hypothesis:

Cause of Depression

A

Low Serotonin –> Medical Depression

Specifically lowered synaptic serotonin

  • Synthesis
    • Tryptophan –> serotonin
  • Packaging
    • Serotonin into vesicles from synthesis
    • or Reuptake (taken from cleft)​
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4
Q

Serotonin

= 5-HT

A
  • Neurotransmitter involved in mood
    • ​also appitite / circadium rhythm
      • neuroendocrine fxn
  • Tryptophan + TRP hydroxylase
    • = 5hydroxytryptophan ​–> Decarboxylase
      • ​= Serotonin
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5
Q

Selective Serotonin Reuptake inhibitors

SSRI

A
  • BLOCK Serotonin Transporters (SERT)
    • on the PRE-synaptic neuron
      • –> INCREASE POST-synaptic concentration of serotonin
  • SERT
    • integral membreane protein
    • Uses NA/K/CL gradients to transport serotonin
      • –> pre-synaptic neuron
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6
Q

Zimeledine

A

First SSRI patended –> for depression

1972

major side effect –> Guillain-Barre Syndrom

  • Found seredipitously
    • ​after searching for drugs similar to brompheniramine
      • an ​antihistamine
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7
Q

Fluoxetine

Prozac

A

SSRI

  • Inhibits SERT, with lower side effects
    • Treat DEPRESSION
      • ​also panic disorder / obesity / alcoholism
  • _​​_In presense of CL- (CL = prozaC)
    • ​is more tightly bound to SERT
  • Sold as a racemate
    • R-enantiomer is more rapidly metabolized/eliminated
  • Derived from DIPHENHYDRAMINE
    • _​a_n antihistamine
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8
Q

Paroxetine

Paxil

A

More Potent SSRI

  • Binds to SERT
    • dependent on SODIUM IONS (NA)
      • not chloride like fluoxetine
  • ​​Mainly treats Depression
    • also treats:
      • panic disorder / social phobia
      • PTSD / SAD / premenstrual dysphoric
      • hot flashes
    • few side effects except suicide
  • ​Lipophilic & enantiomerically pure
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9
Q

Citalopram

Celexa

A

Most Selective SSRI (Ki = 4nM)

  • Treats Depression
    • and anxiety / OCD / panic disorders
    • body dysmorphic disorder / dysthymia
  • RACEMATE
    • just like fluoxetine
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10
Q

More Potent enantiomer of Citalopram

A

S-enantiomer + its metabolite

= More potent inhibitor of 5-HT reuptake

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11
Q

Priviledged Structure of SSRI’s

A
  • Have HIGH affinity for biologic amine transporters
    • ​NET / SERT / DAT
    • ​norepinphrine / serotonin / dopamine
  • Cause for some side effects
    • ​since they are similar to endogenous structures
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12
Q

2-Position of Aryoxyl Structure

A

Atomoxetine / Reboxetine

  • Shows greater selectivity & affinity for NET
    • norepinephrine transporter
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13
Q

4-Position of Aryoxyl Structure

A

Fluoxetine / paroxetine

  • Show more selectivity and affinity for SERT
    • serotonin transporters
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14
Q

SSRI Pharmacophore Features

A
  • PI PI Interactions
    • has 2 aromatic rings
    • Tyr95 / Tyr176
  • 1 hydrophobic feature
    • Ile172 / Phe335
  • Salt Bridge
    • One cationic feature
    • Asp98
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15
Q

Homology Modeling

A
  • Used for SSRI Pharmacophore to discover similar drugs
  • LeuT
    • Prokaryotic leucine transporter
    • similar to hSERT
      • considered as a neurotransmiter sodium symporter
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16
Q

Homology Between

Paroxetine & Fluoxetine & Citalopram

A

still have similar hydrophobic & Pi Pi interactions

  • Paroxetine
    • Salt bridge is formed with piperidine nitrogen amine
      • ​–> ASP98
  • ​​Fluoxetine
    • ​Salt bridge is formed with positively charged nitrogen atoms
      • –>ASP 98
  • ​​Citalopram
    • same as fluoxetine
17
Q

SSRI

Allosteric Modulation

A

SSRI blocks a conformational change

causes a differnce in interactions with serotonin or chloride

not blocking the binding spot

18
Q

SSRI Clinical Lag

4-6 Weeks

A
  • Blocking the-reuptake of serotonin:
    • Takes time for the serotonin to build up
    • BUT SOMETHING ELSE OCCURS
      • ​because RAT EXPERIMENT
      • shows that they respnd immediately to antidepressants
19
Q

Theory for Clinical Lag in SSRI’s

A
  • 5HT depletion INDIRECTLY causes an INCREASE in BDNF
    • ​& BRAIN REMODELING
      • increased functional synapses
  • 4-6 Weeks to respond
    • ​Since there is less serotonin being re-uptakin
      • –> over time more pre-synaptic serotonin receptors are created
20
Q

Pharmacoketics & Toxicity

of SSRI’s

A

​2D6

  • Fluoxetine
    • ​non-linear PK’s
  • Paroxetine (elim by kidneys)
    • ​Linear @ High dose
    • non-linear @ low dose
  • Citalopram
    • only linear PK’s

MedChem Final (8 decks)

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