Term
TCAs - norepinephrine-serotonin reuptake inhibitors
general structural properties |
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Definition
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all have a tricycle system:
2 aromatic rings and a center 7 member ring
6-7-6 system
the tricycle ring may or may not be substituted
side chain:
all substituted at the same position
all have a tertiary amine 3 carbons away from the tricycle system |
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Term
TCAs - selective norepinephrine reuptake inhibitors
general structural properties |
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Definition
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tricyclic system:
2 aromatic rings
6-7-6 system except for maprotiline
tricyclic ring may or may not be substituted
side chain:
SECONDARY AMINE
amoxepine - not linear but is still a secondary amine and is still 3 atoms away from the tricycle AND the side chain is at a different position compared to the others |
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Term
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Definition
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tricyclic ring system
SIDE CHAIN:
basic terminal amino groups (3C chain); secondary and tertiary amines
secondary amines are more NE selective
tertiary amines: NET and SERT inhibitors; in vivo there is an N-demethylation that turns them into secondary amines
branching reduces affinity, but will not completely lose affinity
geometry in TCAs is important for selectivity and affinity
ANTIPSYCHOTIC VS. ANTIDEPRESSANT ACTIVITY:
should be able to look at a structure and determine if it is an antipsychotic or an antidepressant
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in the phenothiazines (antipsychotics) the CIS form is more active
having an O in the seven member ring breaks the symmetry; if it is a C, then the molecule is symmetrical (the O draws the N towards it into the correct position)
BLUE is the GOOD antidepressant WITH antipsychotic activity (CIS)
RED is TRANS and is BAD for antipsychotic activity
ring system not related to SERT or NET inhibition; important for dopamine receptors
halogen or cyano group = SERT
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antipsychotic activity = dopamine antagonism
best position for a substitution (for antispychotic activity) = position 2!!!
electron withdrawing groups help with antidepressant effect and antipsychotic effects
CONFORMATION AFFECTS ANTIPSYCHOTIC ACTIVITY
CONFORMATION DOES NOT AFFECT ANTIDEPRESSANT ACTIVITY
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for the antidepressant activity, it is not necessary to have a planar molecule
phenothiazine: closest to planarity = antipsychotic acitivty (dopamine receptor activity)
addition of the brige in dibenzobicyclooctadiene breaks the planarity of the system and makes it a better antidepressant
substituent on position 2:
electron withdrawing groups -> antipsychotic activity
N or sp2C not required for antidepressant activity
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6-6-6 system: no antidepressant activity IF PLANAR
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addition of the bridge breaks the planarity = antidepressant activity |
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Term
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Definition
common routes:
N-demethylation
aromatic hydroxylation
"bridge" hydroxylation
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all the TCAs that are tertiary amines will have a secondary N-demethylated metabolite that will have antidepressant activity as well
NOR/DES/DESMETHYL prefixes means it has lost 1 methyl group
amitriptyline -> nortriptyline
clomipramine -> desmethylcomipramine
doxepine -_ desmethyldoxepine
imipramine -> desipramine
maprotiline -> desmethylmaprotiline
amoxepine -> 8-OH-amoxepine
desimpramine -> 2-OH-desipramine
nortriptyline -> 10-OH-nortriptyline |
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Term
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Definition
narrow therapeutic window
overdose: prolongation of QRS and QT interval
side effect associated with binding at many different receptors:
sedation
anticholinergic effects
hypotension
CARDIAC EFFECTS
weight gain |
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Term
MOA of Venlafaxine
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Definition
non-TCA norepinephrine-serotonin reuptake inhibitor
preferential affinity for SERT (30 times)
O-desmethyl metabolite has the same pharmacological profile (NOT N-desmethyl)
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Term
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Definition
non-TCA norepinephrine-serotonin reuptake inhibitor
5 times preferential inhibition of SERT
bioisosteric replacement of fluoxetine
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Term
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Definition
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losing the bridge between the 2 aromatic rings = open TCA
N in the phenyl ring
tertiary amine 3 carbons away fromt he system
electron withdrawing group (Br)
MORE SELECTIVE towards serotonin reuptake transporters |
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Term
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Definition
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Term
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Definition
phenoxyphenylakylamines
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only the phenoxy group can be substituted
substitutions in the para (4) position = serotinergic selectivity
substitutions in the ortho (2) potition = NE selectivity
di-substitutions = loss of selectivity (but not activity)
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semirigid analogs (paroxetine):
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alkyl chain is a cycle = semirigid
loss of affinity; retention of selectivity for SERT |
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Term
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Definition
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phenylspiro-benzofuran nucleus: benzyl-furan is like a phenyl ring (bioisotere)
S-citalopram is the active isomer:
red = chiral center
is the most selective SSRI in the market |
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Term
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Definition
[image]
constrained form (fluoxetine)
semirigid: part of the side chain is in a ring limiting the number of conformations the drug can have
2 chiral centers (red)
the SERT affinity is reduced by:
alkylation of the secondary amine
changes on the position of F |
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Term
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Definition
ACTIVE desmethyl metabolites:
citalopram -> desmethylcitalopram
fluoxetine -> norfluoxetine
sertraline -> desmethylsertraline
venlafaxine -> O-desmethylvenlafaxine |
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Term
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Definition
relatively safe in overdose
overdose symptoms: nausea, agitation, seizures, loss of consciousness
SSRIs may impair platelet function
relatively NO cardiac ADRs (as compared to TCAs) |
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Term
| properties of the MAO enzyme |
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Definition
MAO-A
preferred substrates: NE, epinephrine, and serotonin
MAO-B
preferred substrates: tyramine, phenylethylamine, and benzylamine
MAO-A and MAO-B
dopamine and tryptamine |
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Term
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Definition
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Fl = flavin
one electron mechanism:
electron transfer to flavin generating a radical
the radical undergoes rapid cleavage and a double bond is formed
the double bond interacts with the enzyme forming a covalent bond (irreversible) attachment to the cysteine residue
the MAO is COMPLETELY INHIBITED
the only way that MAO can be used again is if it is regenerated |
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Term
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Definition
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selectivity: MAO-A vs. MAO-B
MAO-B = selegeline and rasagiline
RIMAs (reversible MAOIs) = moclobemide and brofaromine (not available in the US)
"wash-out" of RIMAs: shorter than other MAO-Is
normally MAO needs a long time to be regenerated (2-4 weeks) |
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Term
| metabolism of meclobemide (MAO-I) |
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Definition
meclobemide -> lactam
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Term
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Definition
sleep problems
orthostatic hypotension
GI disturbances
sexual disturbances
overstimulation (anxiety)
NO cardiac effects |
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Term
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Definition
food interactions (cheese and wine effect)
tyramine or tryptophan containing food
prescription and non-prescrition drugs |
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Term
| example serotonin receptor modulators |
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Definition
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Term
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Definition
nefazodone and trazodone are weak inhibitors of SERT and NET
nefazodone and trazodone: high affinity for 5HT-2A (antagonists)
trazodone metabolite: 5HT-2C agonist
5HT-1 and mixed function ligand = partial agonist/antagonist |
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Term
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Definition
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small or no N4 substituent: 5HT-1A affinity
aryl portion can be widely variable
doesn't matter what type, BUT HAS TO BE AROMATIC
can be bicyclic as long as it is AROMATIC
unbranched spacer (2-5 carbons long)
terminus: aromatic or heteroaromatic, imide or amide
bulky region modifies functional activity
PIPERIZINE RING (6 member ring with 2 Ns) is COMMON for all |
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Term
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Definition
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nucleophile will open the epoxide group and cause hepatotoxicity |
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Term
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Definition
nefazodone DOES NOT equal trazodone
trazodone:
effects related to the 5HT and alpha1 antagonism (sedation and hypotension)
sexual dysfunction (decreased libido, erectile dysfunction, and anorgasmia)
nefazodone:
safer but potent inhibitor of CYP3A4
does not form an active metabolite |
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Term
MOA of mirtazepine
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Definition
enhanced central noradrenergic and serotonergic activity
very little affinity for SERT or NET
antagonism of serotonergic receptors = antidepressant activity |
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Term
metabolism of mirtazepine
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Definition
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N-demethylation
ring hydroxylation
N-oxide
glucuronidation of metabolites |
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Term
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Definition
DAT inhibitor
used for smoking cessation treatment |
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Term
metabolism of bupropion
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Definition
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tert-butyl inhibits dealkylation
other metabolites:
hydroxypropion (hydroxylation of the tert-butyl group)
reduction of the aminoketone
ALL THE METABOLITES ARE ACTIVE
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