Medicinal Chemistry of Hypnotics

What are hypnotic drugs, and how do they differ from anxiolytics?

Hypnotics produce drowsiness and promote sleep, causing more CNS depression than anxiolytics.

Hypnotics target α1 GABAA subunits (sleep), while anxiolytics target α2 and α3 (anxiety).

What are the main classes of hypnotics, with one example each?

Benzodiazepines (diazepam), Z-hypnotics (zolpidem), melatonin receptor agonists (ramelteon), antihistamines (diphenhydramine), TCAs (doxepin), orexin receptor antagonists (suvorexant)

What substitutions affect benzodiazepine activity?

Larger than -CH₃ decreases activity; electron-withdrawing groups (EWG) increase activity; -OH decreases activity by reducing lipophilicity and half-life.

What structural features are key for benzodiazepine activity?

Most active have a C=O (except with heterocycles); Ring C not required but aids hydrophobic/steric interactions.

How are benzodiazepines absorbed and distributed?

Readily absorbed orally, easily distribute into the CNS.

How does the formation of active metabolites affect benzodiazepines?

Duration of action is prolonged by the formation of active metabolites.

How does a 1,4-triazole ring affect benzodiazepine metabolism?

Prevents oxidative metabolism, leading to a shorter duration of action.

What are the PK categories of benzodiazepines based on half-life?

Long-acting (>24h, e.g., diazepam), intermediate-acting (12-24h, e.g., lorazepam), short-acting (<12h, e.g., triazolam).

What are the key PK and metabolism features of Z-hypnotics?

Selectively bind to α1 GABAA subunit, lipophilic, pass BBB, metabolized in the liver to water-soluble metabolites.

How do melatonin receptor agonists like ramelteon function as hypnotics?

Act as agonists of MT1 and MT2 melatonin receptors to promote sleep; metabolized in the liver (assumed via CYP enzymes).

How do antihistamines like diphenhydramine function as hypnotics?

Block H1 receptors, causing sedation as a side effect.

Why do first-generation ethanolamine ether H1-receptor antagonists have sedative effects?

They cross the blood-brain barrier (BBB) and cause sedative side effects.

How do TCAs like doxepin function as hypnotics?

Inhibit 5-HT and NE reuptake, bind to H1 receptors, causing sedation; doxepin has high H1 receptor affinity.

What are orexins, and how do orexin receptor antagonists like suvorexant work?

Orexins (A and B) are neuropeptides that promote wakefulness via OX1R and OX2R; antagonists like suvorexant block these receptors to promote sleep.

What are the PK properties of suvorexant?

82% oral bioavailability, 99% plasma protein bound, excreted in feces, elimination half-life of 12.2 hours.

How is suvorexant metabolized?

Primarily by CYP3A4 to an inactive hydroxylated metabolite, then to a benzoic acid derivative.

What are the GABAA receptor binding sites for hypnotics vs. anxiolytics?

Hypnotics (e.g., benzodiazepines, Z-hypnotics) target α1 for sleep; anxiolytics target α2 and α3 for anxiety.

How does the metabolism of long-acting vs. short-acting benzodiazepines differ?

Long-acting (e.g., diazepam) have active metabolites; short-acting (e.g., triazolam) are directly metabolized via Phase II conjugation.

What is the role of the α1 subunit in hypnotic action?

The α1 subunit of GABAA receptors is targeted by hypnotics like Z-hypnotics and benzodiazepines to induce sleep.

How do TCAs and antihistamines overlap in their hypnotic mechanism?

Both bind to H1 receptors (e.g., doxepin, diphenhydramine), causing sedation as a side effect.