Z-drugs

Z-drugs are sleep medicines without broadly-accepted mechanism of action, clinically similar to benzodiazepines.

Like melatonin and melatonin-analogues (top row), zolpidem and zopiclone share an adenosine-similar almost-6-nitrogen.

Zolpidem, zopiclone, and diazepam (a benzodiazepine) directly activate adenosine receptors in guinea pigs (well-preserved across evolutionary tree): PMID 1676693.*

Diazepam’s purine-similarity is clarified by comparison with other benzodiazepines, e.g. triazolam (Halcion). Note that the suffix
-lam denotes the presence of a 5-member ring adjacent to the standard 7-member ring that can be used for orientation.

Zolpidem and zopiclone activate adenosine receptors.

Diazepam activates adenosine receptors and also prolongs adenosine response, likely by inhibiting the sole adenosine breakdown enzyme, adenosine deaminase: PMID 1676693.

Zolpidem and zopiclone are generally accepted as unhelpful in bipolar disorder and are absent from APA bipolar treatment guidelines. There are several case reports of zolpidem- induced bipolar mania (PMID 31071363).

Benzodiazepines (BZD) like diazepam are helpful in bipolar treatment (top level evidence in APA guidelines), potentially due to adenosine deaminase inhibition increasing adenosine, reversing the underlying purine imbalance.

Increase risk of seizure following treatment with zolpidem 25373122

Zolpidem for seizures in mice 18217189 IMG