CNS Depressants & Antipsychotics – Organic Medicinal Chemistry Review

Vocabulary flashcards covering structural activity relationships, key drugs, and pharmacological principles of CNS depressants (anxiolytics, sedative-hypnotics) and antipsychotics.

Anxiolytics

Drugs that depress the central nervous system to reduce anxiety.

Classes of Anxiolytics

Classes include Benzodiazepines, Barbiturates, and GABA Agonists.

Benzodiazepine SAR – EWG halogens

Electron-withdrawing halogens (e.g., Cl) at the 7-position increase CNS depressant activity.

Benzodiazepine SAR – Hydroxyl group (- ext{OH})

Presence of an ortho-hydroxyl group decreases duration of action by promoting rapid conjugation.

Benzodiazepine SAR – Triazolo ring

Benzodiazepine fused with a triazole ring leading to shorter duration of action; example: Alprazolam, Triazolam.

Benzodiazepine SAR – Imidazole ring

Benzodiazepine fused with an imidazole ring (e.g., Midazolam) that shortens duration of action and allows parenteral use.

Flumazenil

An antidote for benzodiazepine overdose.

Barbiturates SAR – Increasing lipophilicity

Increasing lipophilic substituents enhances hypnotic potency and speeds onset but shortens duration.

Barbiturates SAR – Replacement of sulfur

Substituting oxygen with sulfur at C-2 increases lipophilicity and speeds onset, hence rapid onset of action and increased hypnotic activity (e.g., Thiopental).

Barbiturates SAR – Alkyl groups

Addition of alkyl groups at C-5 increases lipophilicity, hypnotic potency, and speed of onset.

Alcohol – CNS depressant potency

Depressant potency of alkanols increases up to eight carbon atoms, then declines.

Alcohol Potency Order

Tertiary > Secondary > Primary (or Primary < Secondary < Tertiary) alcohols in CNS depressant potency.

Glutethimide

Non-barbiturate hypnotic structurally similar to barbiturates; strong enzyme inducer (CYP450).

Mephensin – Guaifenesin

Guaifenesin is an expectorant structurally related to Mephensin; Mephensin is a muscle relaxant.

Mephensin – Methocarbamol (CONH₂ group)

Carbamate derivatives (e.g., methocarbamol) of Mephensin increase sedative–hypnotic activity.

Chloral Hydrate

Sedative converted rapidly to trichloroethanol (active metabolite); ethanol increases NADH, enhancing reduction to trichloroethanol.

Chloral Hydrate + Ethanol

Synergism: Ethanol elevates NADH, enhancing reduction of chloral to trichloroethanol; combined use greatly increases CNS depression.

Chloral Hydrate Irritation

Compound is acidic and can cause gastric mucosal irritation.

Cause of Psychosis

Excess dopamine activity underlies psychotic symptoms.

Solution for Psychosis

Treatment aims to reduce dopamine signaling by blocking dopamine receptors.

Phenothiazine SAR – EWG halogens at R

Electron-withdrawing halogen on the aromatic ring enhances antipsychotic activity.

Phenothiazine SAR – Chain modification

Optimal distance between ring nitrogen and terminal amine is a three-carbon chain; alteration (shortening/lengthening) decreases antipsychotic potency.

Chlorpromazine

First phenothiazine introduced clinically; prototype typical antipsychotic.

Haloperidol

Potent typical antipsychotic; produces extrapyramidal symptoms (EPS) due to strong D2 blockade.