Term
| anxiolytic vs. hypnotic effects of benzodiazepine |
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Definition
the target of BDZs is the GABA-A receptor
HYPNOTIC:
rapidly absorbed
high lipophilicity (faster onset of action as they will cross the BBB quickly)
active metabolites that are slowly eliminated (or no active metabolites)
ANXIOLYTIC:
slow absorption (prolonged duration of action b/c it takes them longer to get into the CNS)
active metabolites
low lipophilicity |
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Term
| benzodiazepines structure, Class A |
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Definition
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Term
| benzodiazepines structure, Class B |
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Definition
[image]
includes a third heterocycle fused to the bicyclic system |
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Term
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Definition
[image]
RING A:
pi-pi stacking - receptor interactions through the phenyl ring
electronegative substituent (Cl, NO2) at 7 position (does not interfere with the pi interactions)
only can have a substitutent in POSITION 7; any other place will lose activity
heterocycle (piperidine for example) = weak binding; pi-pi interactions will be different
RING B:
proton accepting group required (N)
replacement of O for S = still anxiolytic (S will increase lipophilicity)
3-position: affect antagonistic but not agonistic affinities
4-N substitution affects antagonistic but not agonistic affinities
1-N: substitution no required; eliminating the methyl group on the N = ACTIVE METABOLITE (not needed for activity)
double bond and N position can change
RING C:
not required for receptor binding (but improves physicochemical properties of the BZD)
PLANARITY is NECESSARY for binding
Substitutions:
para = unfavorable
ortho = affinity increased if electron withdrawing |
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Term
metabolism of chlordiazepoxide
[image] |
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Definition
[image]
many active metabolites |
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Term
metabolism of quazepam
[image] |
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Definition
[image]
2-Oxo (sulfur is replaced by O)
N-desalkyl
ACTIVE METABOLITES |
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Term
metabolism of triazolam
[image] |
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Definition
[image]
hydroxymethyl
50% active |
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Term
metabolism of flurazepam
[image] |
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Definition
[image]
N-desethyl
ACTIVE METABOLITE |
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Term
metabolism of estazolam
[image] |
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Definition
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Term
| structural classifications of non-benzodiazepine GABA-A receptor modulators |
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Definition
imidazopyridines - zolpidem
[image]
cyclopyrrolones - eszopiclone (lunesta)
[image]
pyrazolopyridines - zalplon (sonata)
[image] |
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Term
properties of imidazopyridines
[image] |
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Definition
[image]
alpha-1 subunit selective on the GABA-A receptor
anxiolytic activity = typical BZD
weak anticonvulsant activity |
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Term
metabolism of zolpidem
[image] |
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Definition
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Term
properties of cyclopyrrolones
[image] |
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Definition
[image]
exzopiclone (lunesta)
"superagonist"
s-enantiomer
extensive CYP metabolism
metabolites primarily excreted in the urine |
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Term
metabolism of eszopiclone
[image] |
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Definition
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Term
properties of pyrazolopyrimidines
[image] |
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Definition
[image]
high affinity to alpha-1 containing GABA-A receptors
zaleplon is effective to decrease sleep latency
indiplon has not been approved and its status is unclear
ocinaplon trials have been discontinued due to liver toxicity |
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Term
metabolism of zaleplon
[image] |
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Definition
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Term
| properties of the melatonin receptor agonist ramelteon |
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Definition
[image]
s-isomer more active
methyl orientation is critical
the top structure of melatonin is the active form
ramelteon has locked the active conformation with a ring system
M1 selective |
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Term
metabolism of ramelteon
[image] |
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Definition
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Term
properties of amphetamine related agents
[image] |
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Definition
"stimulants" or "behavioral stimulants"
phenylisopropylamines
[image]
dopaminergic and noradrenergic agonst -> increase dopamine release and prevents reuptake
"amphetamine psychosis" |
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Term
| amphetamine related agents SAR |
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Definition
PHENYL RING
[image]
any substitution will decrease or abolish amphetamine like activity
4-OH (not active) -> 4-OCH3 (weak stimulant)
4-CH3 (weak stimulant)
4-Cl (5HT releasing agent - antidepressant)
3-CF3 - appetite suppressant
AMINE SUBSTITUTION
[image]
NH2>NHR>NR2
primary amines are the best for stimulant activity, then secondary amines, then tertiary amines (least activity)
EXCEPTION: methamphetamine is a secondary amine
for NHR = activity decreases when length increases
ALPHA SUBSTITUTION
[image]
demethylation decreases lipophilicity and increases susceptibility to metabolism by MAO
increased length decreases stimulant activity
S>R (only for central stimulant effect)
BETA SUBSTITUTION
[image]
OH: ephedrine and NE
OH: decrease central stimulant effect (low BBB penetration)
keto: retain potency |
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Term
metabolism of amphetamine
[image] |
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Definition
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Term
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Definition
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