CNS Depressants & Anti seizure Drugs

Question 1

-Drugs that can be used to slow down or depress the functions of the CNS
-often share at least one mode of action: positive modulation of the action of y-aminobutyric acid (GABA) at GABA (A) receptor complex

Answer 1

CNS DEPRESSANTS

Question 2

-aka Anxiolytics
-reduce anxiety and exert a calming effect

Answer 2

Sedatives

Question 3

-produce drowsiness & encourage the onset & maintenance of a state of sleep
-involve more pronounced depression of the CNS than sedation

Answer 3

Hypnotics

Question 4

-major inhibitory neurotransmitter in the brain
-deficiency of its activity in the CNS is important in the pathophysiology of Anxiety & Insomnia
-activate 2 types of receptors:
*the inotropic GABA (A & C) receptors
*the metabotropic GABA (B) receptor

Answer 4

gamma aminobutyric acid (GABA)

Question 5

-target for many Anxiolytics and Sedative- hypnotic agents
-ligand-gated Chloride ion channel
-upon activation, Cl- influx is increased & the membrane becomes Hyperpolarized, resulting in Neuronal Inhibition

Answer 5

GABA (A) receptors

Question 6

GABA (A) receptor
Agonists

Answer 6

Benzodiazepines

Question 7

GABA (A) receptor
Inverse Agonists

Answer 7

beta carbolines

Question 8

GABA (A) receptor
Antagonist

Answer 8

Flumazenil

Question 9

increase the Frequency of opening of the chloride ion channel

Answer 9

GABA (A) receptor Agonist: Benzodiazepines MOA

Question 10

-diminish the positive effect of GABA on chloride flux
-increase anxiety, produce panic attacks, & improve memory

Answer 10

GABA (A) receptor Inverse Agonist: Beta Carbolines

Question 11

-used clinically to counteract the Sedative effect of Benzodiazepine overdose

Answer 11

GABA (A) receptor Antagonist: Flumazenil

Question 12

SAR of Benzodiazepine

Answer 12

• 1-NR group is optimal for activity
• H-accepting group ↑ the activity
• 2-C=O is important for activity
• 1,2 fused triazole or imidazole ring ↑ the activity (short acting)

*substitution with a 3-OH group ↔ the activity with 3-OH group:
polar, readily converted to the excretable glucoronide →↓ DOA (short acting)
w/o 3-OH group:
non-polar, undergo hepatic oxidation & active metabolite →↑ DOA (long acting)

• 5phenyl group ↑ activity

*2’ or 2’, 6’ substituted w/ EWG ↑ activity
4’ substitution ↓↓ activity

*7’ EWG required:
↑ electronegativity → ↑activity
position 6,8,9 should NOT be substituted

*effects of ring A on activity:
aromatic ring > heteroaromatic ring

*a phenyl ring at pos 5 promotes activity
if orto (2) or diorto (2,6) substituted w/ EWG = increases activity
if para substitution = ↓ activity

Question 13

short acting benzodiazepines

Answer 13

Triazolam
Midazolam

Question 14

intermediate acting benzodiazepines

Answer 14

Alprazolam
Estazolam
Lorazepam
Temazepam
Oxazepam

Question 15

long acting benzodiazepines

Answer 15

Clorazepate
Chlordiazepoxide
Clonazepam
Diazepam
Flurazepam
Quazepam

Question 16

non benzodiazepine BzRAs
Z drugs

Answer 16

Zolpidem
Eszopiclone
Zaleplon

Question 17

↑ log P =

Answer 17

↑ lipophilicity

Question 18

an imidazopyridine

Answer 18

Zolpidem

Question 19

-a cyclopyrrolone (ketone)
-Zopiclone: racemic mixture
-S-isomer: primary active hypnotic

Answer 19

Eszopiclone

Question 20

a pyrazolpyrimidine

Answer 20

Zaleplon

Question 21

-play a role in the Circadian Rhythm of humans
-biosynthesized & released at night
-promoted commercially as a Sleep Aid by the food supplement industry
-Poor Hypnotic Drug (poor potency, poor absorption, poor oral bioavailability, rapid metabolism, & non-selective effects)

Answer 21

Melatonin

Question 22

n-acetylated & o-methylated product of serotonin found in the pineal gland
*an endogenous sleeping neurohormone

Answer 22

Melatonin

Question 23

precursor of melatonin
aka 5-HT

Answer 23

Serotonin

Question 24

-activate melatonin receptors
-more efficacious than melatonin but less efficacious than benzodiazepines as a hypnotic

Answer 24

Ramelteon

Question 25

-are 5,5-disubstituted barbituric acids -increase the duration of the GABA-gated chloride channel openings

Answer 25

Barbiturates

Question 26

SAR of Barbiturates

Answer 26

* 5,5- disubstituted are important for activity & duration of action * R1=alkyl →↑ lipophilicity → quicker onset & shorter DOA * O → S → ↑ lipophilicity → rapid onset *must be a weak acid * the barbituric acid is 2,4,6-trioxohexahydropyrimidine, w/c lacks CNS depressant activity *replacement of both hydrogens at pos 5 with alkyl or aryl groups confers the activity

Question 27

in general, increasing lipophilicity *increases hypnotic potency *faster onset f action *shorter duration of action

Answer 27

SAR of Barbiturates

Question 28

increasing the number of carbon atoms at the R5 position

Answer 28

increases lipophilicity SAR of barbiturates

Question 29

*branching *unsaturation *replacement of alicyclic or aromatic substituents for alkyl substituents *introduction of halogen into the alkyl substituents all

Answer 29

increase the lipid solubility of the barbituric acid derivatives

Question 30

addition of alkyl group at R1 = increases lipophilicity results to

Answer 30

quicker onset & shorter DOA

Question 31

replacement of oxygen by sulfur at pos 2 (thiobarbiturates) = increases lipophilicity =

Answer 31

ultra-short acting barbiturates (used as anesthetics, not as sedative-hypnotics)

Question 32

ultra short acting barbiturates -not sedative or hypnotics -used as anesthetics

Answer 32

Thiopental Thiamylal

Question 33

short acting acting barbiturates -sedatives

Answer 33

Pentobarbital Secobarbital

Question 34

intermediate acting barbiturates -hypnotics

Answer 34

Amobarbital Butabarbital

Question 35

Long acting barbiturates -anti-convulsants

Answer 35

Mephobarbital Phenobarbital

Question 36

miscellaneous Sedative - Hypnotics

Answer 36

* Amides & Imides * Alcohol & their Carbamate Derivatives * Aldehydes & their Derivatives

Question 37

structurally similar to the barbiturates, especially phenobarbital

Answer 37

Glutethimide