IDT - Anxiolytics & Sedatives Medchem

Question 1

Answer 1

Non-Benzodiazepine Anxiolytic

Buspirone, 5-HT1A agonist

Targets 5-HT1A receptor,

Metabolism by 3A4 (Both Active)

1. Dealkylation of N-pyrindyl-piperazine rings
2. Hydroxylation of 6 membered ring.

Question 2

Answer 2

Benzodiazepine SAR

A,B - 6 and 7 membered ring, EWG @ 5

7 required EWG (more withdrawing = more potent)

2’ optional EWG (inc potency)

Question 3

Answer 3

BDZ

Chlordiazepoxide

4 - N and 2 group unnecessary for activity

7 - Cl

Extensive Metabolism by de-alkylation and reduction

Question 4

Answer 4

Benzodiazepine

Diazepam

More Lipophilic than Chlordiazepoxide

Fast onset, 5-10 times more potent

Dosed 2-4 times a day (higher dose needed for anxiolytic)

Metabolism (All active Metabolites)

1. 3-hydroxydiazepam (Temazepam)
2. N-desmethyldiazepam (Nordazepam)
3. 1 and 3 progress to Oxazepam

Question 5

Answer 5

Benzodiazepines

Clorazepate

Prodrug form of Nordazepam, Oxazepam

Metabolism

1. Decarboxylation into Nordazepam
2. Nordazepam hydroxylated into Oxazepam
3. Oxazepam Glucoronidated

Question 6

Answer 6

Benzodiazepine

Lorazepam

Extra 2’ EWG

More potent than Oxazepam

Metabolism

1. Direct Glucoronidation (inactive metabolite)

Question 7

Answer 7

Benzodiazepene

Alprazolam

Triazole Ring

Metabolism by Cyp 3A4 (both inactive rapidly glucoronidated)

1. 4-hydroxyalprazolam
2. alpha-hydroalprazlam

T1/2 - 12hrs

Question 8

Answer 8

Benzodiazepene

Clonazepam

Also used for Epilepsy and Panic disorders

Metabolism

1. Reduction of Nitro group - 2-aminoclonazepam (inactive)

T1/2 - 34hrs

Question 9

Answer 9

Benzodiazepine

Quazepam

To treat Insomnia

2-Thio, 2’ Fluoro

Metabolism

1. 2-oxoquazepam (active) (T1/2 - 40hrs)

T1/2 - 33hrs

Question 10

Answer 10

Benzodiazepine

Midazolam

Used for Preoperative sedation (induction of anesthesia)

Metabolism

1. alpha-hydroxylation (active)
2. Alpha-hydroxylation gluronidated (inactive)

T1/2 - 2hrs

Question 11

Answer 11

Benzodiazepine

Triazolam

Used as a Sedative

Metabolism by 3A4 both rapidly glucoronidated (inactive)

1. 4-hydroxylation
2. alpha-hydroxylation

Question 12

Answer 12

Benzodiazepine

Flumazenil

Lacks 5 phenyl group of BDZ agonists, Used IV

Metabolism

1. Rapid Ester Hydrolysis

T1/2 - 1hr

Question 13

Answer 13

Barbituate SAR

Salt form, for IV or Inj = more hydrophilic

Needs 5,5 distribution for sedative action

Needs 5,5-dialkyl for sedative/hypnotics

C-5 (7-9) for peak sedation

If C-5 too lipophilic, poor solubility

if C-5 # too high, decrease duration

Branching or unsaturation at C-5 = inc activity dec duration/toxicity

Question 14

Answer 14

Barbituate

Butabarbital

Duraion = 6-8hrs

Butane at C-5 (6 carbons total)

Question 15

Answer 15

Barbiturate

Secobarbital

C-5 = 8

Unsaturation in side chain

Increased sedative effect, reduced duration

Question 16

Answer 16

Barbituate

Methohexital

C-5 = 9

N-methyl group, and extra unsaturation

Very lipophilic, increased activity

Rapid action, used to induce anesthesia (IV)

Question 17

Answer 17

Misc Sed/Hyp

Chloral Hydrate

Metabolism

Aldehyde Hydrate <+H20-> Tichloralactaldehyde

1. Trichloralacetaldehyde –NADH–> Trichloroethanol (Active)

Question 18

Answer 18

Misc Sed/Hypn

Meprobamate

(Bicarbamate, propyl, methyl)

No active Metabolite

(structurally similar to Carisoprolol (muscle relaxer))

Question 19

Answer 19

Z-drugs

Zolpidem Tartrate

Treat Insomnia, bind to GABAa receptors w/ alpha-1

Metabolism by 3A4

1. Aromatic ring methyl oxidation
2. 1) –> Aromatic ring carboxylate

Question 20

Answer 20

Z-drugs

Zaleplon

Insomnia

Metabolism

1. (Major) Oxidation by Aldehyde Oxidase
2. (Minor) Deehtylzaleplon by 3A4
3. interaction w/ Cimetidine (H2 antag), increase T1/2

Question 21

Answer 21

Z-Drugs

Eszopiclone

Insomnia

Metabolism (inactive metabolites) by 3A4

1. N-Desmethylzopiclone
2. Eszopiclone N-Oxide

Question 22

Answer 22

Melatonin

Endogenous Neurotransmitter

Produced by Pineal Gland for Circadian rhythm cycles

Question 23

Answer 23

Melatonin Receptor

Ramelteon

Core Indole mimc

MT1 and MT2 agonist

Metabolism by 1A2 and 2C19

1. Hydroxyramelteon Metabolite (inactive)

Question 24

Answer 24

Melatonin Receptor Agonist

Tasimelteon

Core Indole mimic

To treat non 24-hour sleep.wake (blind people)

Metabolism by 1A2 and 3A4

1. Hydroxy Metabolite (inactive)

Question 25

Answer 25

Alpha 2 agonist

Demedetomidine

Related to Clonidine and Imidazoline (alpha-2)

Used IV for rapid sedation

Question 26

Answer 26

Orexin Receptor Agonist

Suvorexant (Belsomra)

1st in class

Single R-enantiomer

Metabolism

1. Hydroxylation to an inactive metabolite

Question 27

Answer 27

GABAb receptor

Gamma Hydroxybutyrate (GHB); Sodium Oxybate

To treat excessive day time sleepiness in narcolepsy patients

Sedative drug, very heavily controlled => Date Rape

Prodrug Forms (also Regulated)

1. 1,4 butanediol
2. Gammabutyrolactone