CNS DEPRESSANTS

- An aromatic ring is more preferred than heteroaromatic ring
- Electron withdrawing group is needed at position 7 in order to increase the electronegativity of the molecule; the activity will also increase.

BENZODIAZEPINES
Ring A:

Heteroaromatic

For optimal activity, what type of ring is preferred for Ring A of a benzodiazepine?

Electron- Withdrawing Group

What is required at the 7th position of Ring A for benzodiazepine activity?

It increases activity.

How does increasing electronegativity at position 7 of Ring A affect benzodiazepine activity?

1-NR group (where R is typically alkyl)

What is the optimal group at the 1st position of the benzodiazepine structure for activity?

- Attachment of Hydrogen Accepting group the activity will increase.
- At position 2 the C=O or ketone group is very important for activity.
- 1,2 Fused triazole or imidazole will increase the activity.
- OH at position 3, the resulting compound is more polar, readily converted to an excreted glucuronide conjugate, leading to a shorter DOA.
- If there is no OH at position 3, the compound is more nonpolar, undergoes hepatic oxidation and may form active metabolites, leading to a longer DOA.

BENZODIAZEPINES
Ring B:

C=O or Ketone

What functional group at the 2nd position of Ring B is important for benzodiazepine activity?

Triazole or Imidazole Ring

What fusion at position 1 and 2 of Ring B increases activity?

It generally decreases the DOA because the resulting compound is more polar and readily excreted as a glucuronide.

How does the presence of a 3-OH group on Ring B generally affect the duration of action (DOA) of a benzodiazepine? Why?

It generally leads to a longer DOA because the compound is more nonpolar, undergoes hepatic oxidation, and may form active metabolites.

How does the absence of a 3-OH group on Ring B generally affect the duration of action (DOA) of a benzodiazepine? Why?

- The presence of a 5-phenyl group increases activity.
- Substitution at the 2' or 2',6' positions with an electron-withdrawing group (EWG) increases activity.
- Substitution at the 4' position decreases activity.

BENZODIAZEPINES
Ring C:

Phenyl

What group is present at position 5 of Ring C to increase the activity of benzodiazepines

2' or 2',6'

Substitution at which positions of the 5-phenyl group (Ring C) with an electron-withdrawing group (EWG) increases the activity of benzodiazepines?

4’

Substitution at which position of the 5-phenyl group (Ring C) generally decreases benzodiazepine activity?

- Positions 6, 8, and 9 should not be substituted
- In diazepine ring B, saturation of the 4,5-double bond or a shift of it to the 3,4-position decreases activity
- Alkyl substitution at the 3-position decreases activity; substitution with a 3-hydroxyl does not

BENZODIAZEPINES
Additional Structure-Activity Relationships:

6,8,9

BENZODIAZEPINES
At what positions should not be substituted?

Saturation of the 4,5-double bond
Shifting the double bond to the 3,4-position

BENZODIAZEPINES
What occurs in diazepine Ring B that decreases the activity of benzodiazepines?

Alkyl

BENZODIAZEPINES
What substitution at the 3- position decreases the activity?

Hydroxyl

BENZODIAZEPINES
What substitution at the 3- position does not decrease the activity?

OH

What is the reason for the significant difference between diazepam and temazepam that leads to their different half-lives?

5,5-Disubstituents

What structural feature of barbiturates is essential for their activity and duration of action?

Alkyl

What substitution at the R1 position of a barbiturate increases its lipophilicity, leading to a quicker onset and shorter duration of action?

Increase Lipophilicity
Quicker Onset
Shorter DOA

What effect does an alkyl group at the R₁ position of a barbiturate?

Increase Lipophilicity
Rapid Onset

What effect does the substitution of an oxygen atom with a sulfur atom in a barbiturate?

Thiopental
Thiamylal

CNS Depressants: Barbiturates (Ultra-Short-Acting)

Phenothiazine Antipsychotics

- They possess a tricyclic structure consisting of a 6-6-6 ring system.
- This system is formed by two benzene rings linked by a sulfur atom and a nitrogen atom.

6-6-6

What is the core ring system of phenothiazine antipsychotics?

Two Benzene Rings
Sulfur and Nitrogen Atom

Structural Characteristics of Phenothiazine Ring

2

Which position on the phenothiazine ring is the best for substitution to enhance antipsychotic activity?

3

Which position on the phenothiazine ring can improve activity over nonsubtituted compounds but not as significantly as substitution at the 2- position?

1

Which position (substitution) on the phenothiazine ring has a deleterious effect on antipsychotic activity?

4

Which position (substitution) on the phenothiazine ring has a deleterious effect on antipsychotic activity, although to a lesser extent than substitution at the 1-position?

Electron Withdrawing Groups (Chlorine)

What type of substituent at the 2-position (R₂) of a phenothiazine generally enhances antipsychotic activity?

3- Atom Chain (−CH2​−CH2​−CH2​−)

What is the optimal length of the carbon chain connecting the ring nitrogen (N¹⁰) to the terminal nitrogen in the side chain of phenothiazine antipsychotics?

Promethazine
Diethazine
Ethopropazine

Phenothiazine drug without antipsychotic activity?

Promethazine

What is an example of a phenothiazine drug that has both antihistamine and anticholinergic properties?

Diethazine
Ethopropazine

What is an example of a phenothiazine drug that has antimuscarinic activity?

Benzodiazepines
Barbiturates
Phenothiazine

Examples of CNS Depressants