CNS Depressants & Anti-Seizure Drugs Flashcards
drugs that can be used to slow down or depress the functions of the CNS
CNS depressants
often share at least one mode of action
-positive modulation of the action of y-aminobutyric acid (GABA) at GABAa receptor complex
CNS depressants
aka anxiolytics
reduce anxiety & exert a calming effect
Sedatives
-produce drowsiness & encourage the onset & maintenance of a state of sleep
-involve more pronounced depression of the CNS than sedation
Hypnotics
major inhibitory neurotransmitter in the brain
GABA
deficiency in GABA activity in the CNS is important in the pathophysiology of
anxiety & insomnia
2 types of receptors that GABA activates
1- inotropic: GABA a & c
2- metabotropic: GABA b
-target for many anxiolytics & sedative-hypnotic agents
-ligand-gated chloride channel
upon activation, Cl- influx is increased & the membrane becomes hyperpolarized, resulting in neuronal inhibition
GABAa receptor
GABAa receptor Agonist
increase frequency of opening of the chloride channel
Benzodiazepines
GABAa receptor Inverse Agonist
-diminish the positive effect of GABA on chloride flux
-increase anxiety, produce panic attacks, & improve memory
B-carbolines
-GABAa receptor Antagonist
-used clinically to counteract the sedative effect of benzodiazepine
FLumazenil
benzoDiAzEpines
Di=2
Az=Nitrogen
Ep= 7 membered ring
benzodiazepines
-diazepam
-chlordiazepoxide
-flurazepam
-desmethyldiazepam
-oxazepam
-lorazepam
-nitrazepam
-triazolam
-alprazolam
Aromatic or heteroaromatic ring A on benzodiazepine is
-required for activity
-aromatic ring > heteroaromatic ring
An electronegative substituent at position 7 of Benzodiazepine is required for activity
more electronegative = higher activity
Positions 6, 8, and 9 should NOT be substituted.
SAR of Benzodiazepines
A phenyl ring C at position 5 promotes activity
If ortho (2) or diortho (2,6) substituted with EWG =
increases activity
SAR of Benzodiazepines
A phenyl ring C at position 5 promotes activity
para substitution =
decreases activity
SAR of Benzodiazepines
substitution with a 3-OH group
with 3-OH group: ↓ DOA (short-acting)
without 3-OH group: ↑ DOA (long-acting)
SAR of Benzodiazepines
2-carbonyl (C=O) group =
Nitrogen atom at position 1 (N₁) =
important for activity
SAR of Benzodiazepines
1,2-fused triazole or imidazole ring =
increased activity tolerance
Short acting
Short acting benzodiazepines
Triazolam
Midazolam
Intermediate acting Benzodiazepines
Lorazepam
Temazepam
Oxazepam
long acting benzodiazepines
Clorazepate
chlordiazepoxide
Clonazepam
Diazepam
Flurazepam
Quazepam
Nonbenzodiazepine BzRAs
Zolpidem
Eszopiclone
Zapelon
NONBENZODIAZEPINE BzRAs
Zolpidem
Imidazopyridine
NONBENZODIAZEPINE BzRAs
Eszopiclone
-a cyclopyrrolone
-S-isomer: primary active hypnotic
NONBENZODIAZEPINE BzRAs
Zapelon
a pyrazolopyrimidine
-play a role in the circadian rhythm
-biosynthesized & released by night
-promoted commercially as sleep aid
-poor hypnotic drug
melatonin
-precursor of melatonin
-an indole
serotonin
an endogenous sleeping neurohormone
melatonin
-activate melatonin receptors
-more efficacious than melatonin but less efficacious than benzodiazepines as a hypnotic
ramelteon
are 5,5-distributed barbituric acids
barbiturates
barbituric acid that lacks CNS depressant activity
2,4,6-trioxohexahydropyrimidine
replacement of both hydrogens at _________ with alkyl or aryl groups confers activity
position 5
SAR of Barbiturates
in general, increasing lipophilicity=
-increases hypnotic potency
-faster onset of action
-shorter duration of action
increase in log P=
increase in lipophilicity
SAR of Barbiturates
increasing the number of carbon atoms at the R5 position=
increases lipophilicity
SAR of Barbiturates
unsaturation of the alkyl substituents=
increase the lipid solubility
secobarbital > pentobarbital
SAR of Barbiturates
addition of alkyl group at R1=
increases lipophilicity
SAR of Barbiturates
replacement of oxygen with sulfur at pos 2=
thiobarbiturates
*ultra-short acting barbiturates
*used as anesthetics, not as sedative-hypnotics
thiopental
thiamylal
thiobarbiturates
*ultra-short acting
*anesthetics
pentobarbital
secobarbital
*short acting
*sedatives
Amobarbital
Butabarbital
intermediate acting
*hypnotics
mephobarbital
phenobarbital
long acting
*anti-convulsant
miscellaneous sedative-hypnotics
*amides & imides
*alcohols & their Carbamate derivatives
*aldehydes & their derivatives
structurally similar to the barbiturates, especially phenobarbital
glutethemide
CNS depressant potency increases up to how many carbon atoms?
maximum 8 carbons
decreasing potency if more than 8 carbons
ALCOHOLS AND THEIR CARBAMATE DERIVATIVES
Branching of the alkyl chain
increases depressant activity
tertiary > secondary > primary
ALCOHOLS AND THEIR CARBAMATE DERIVATIVES
Replacement of a hydrogen atom in the alkyl group by a halogen =
increases activity
Carbamylation of alcohols generally
increases depressant potency
thought to act principally through a metabolite
trichloroethanol
combination of ethanol and chloral hydrate
mickey finn
cyclic trimer of acetaldehyde
paraldehyde
*are symptoms of disturbed electrical activity in the brain characterized by episodes of abnormal, excessive, and synchronous discharge of a group of neurons within the brain that cause involuntary movement, sensation, or thought
*may result from primary or acquired neurological disturbances of brain function as a result of an imbalance between excitatory and inhibitory processes in the brain
seizures
derivative of phenobarbital
primidone
5,5-diphenylhydantoin
phenytoin
prodrug of phenytoin
fosphenytoin
oxazolidinediones
trimethadione
dimethadione
succinimides
ethosuximide
methsuximide
iminostilbene
dibenzazepine derivatives
dibenz= 2 benzenes
az= 1 nitrogen
ep= 7 membered ring
carbamazepine
oxcarbazepine
benzodiazepines
2 nitrogens in a 7 membered ring
diazepam
clonazepam
gaba analogues
from the gaba structure
vigabatrin
gabapentin
pregabalin
valproic acid
broad spectrum anticonvulsant
valproic acid
valeric acid
5 carbons
bis-carbamate
felbamate
2 carbamates linked to 1 benzene ring
phenyltriazine
lamotrigine
tri az in= 3 N in 6 membered ring
sulfonamide type anti anticonvulsant
zonisamide
levetiracetam
pyrrolidone derivative
an analog of the nootropic agent- piracetam
tiagabine
nipecotic acid active moiety
