Rilmazolam
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Rilmazolam is a sedative-hypnotic benzodiazepine derivative and the active metabolite of rilmazofone, its prodrug marketed under the brand name Rhythmy (リスミー) in Japan, where it is approved drug for the treatment of insomnia and as a pre-anesthetic medication.[1] Rilmazolam itself has never been developed or approved for medical use in any country.[2]
Chemical and physical data
[edit]A triazolobenzodiazepine is a subset of the benzodiazepine drug class whereby a triazole ring is fused to the diazepine core. Its molecular formula is C19H15Cl2N5O and its molecular weight is 400.26 g/mol.[3][4] The IUPAC name is 8-chloro-6-(2-chlorophenyl)-N,N-dimethyl-4H-[1,2,4]triazolo[1,5-a][1,4]benzodiazepine-2-carboxamide.[5] It is soluble in methanol and chloroform.[4]
Pharmacology
[edit]Rilmazolam acts as a positive allosteric modulator at the GABAA receptor, enhancing the inhibitory effects of gamma-aminobutyric acid (GABA) in the central nervous system. This produces sedative, hypnotic, anxiolytic, and muscle-relaxant effects characteristic of benzodiazepines.[3]
Rilmazolam has been reported to bind to benzodiazepine receptors with a Ki of 2.6 nM, a potency comparable to that of bromazolam (Ki = 2.3 nM).[6][better source needed]
Metabolism and pharmacokinetics
[edit]Rilmazolam is not administered directly, but formed in vivo from its prodrug, rilmazafone. Rilmazafone has negligible, practically inactive, affinity for benzodiazepine receptors. After oral administration, it is metabolized by aminopeptidase enzymes in the small intestine to a desglycylated intermediate (191DG), which then undergoes spontaneous, non-enzymatic cyclization to form rilmazolam. This activation occurs during a single passage through the intestinal wall.[1] Oral administration of rilmazafone in humans produces at least five active metabolites: M-1 being rilmazolam, as well as M-2, M-A, and M-3; unlike in animals, M-4 is the major metabolite in human plasma for up to six hours after dosing.
The parent compound, rilmazafone, is not detectable in human plasma after common therapeutic doses of 1–2 mg. Urinary excretion is primarily as M-4, with 44–68% of the dose recovered in urine within 24 hours. Other metabolites and their conjugates account for less than 1% of the dose.[7][full citation needed] Rilmazolam is further metabolized to N-desmethylrilmazolam, which is also an active metabolite.[8]
Toxicity and adverse effects
[edit]As a benzodiazepine, rilmazolam can cause dose-dependent central nervous system depression, including sedation, impaired motor coordination, memory impairment, and next-day residual "hangover" effects. Overdose may lead to respiratory depression, coma, and death, particularly when combined with other central nervous system depressants such as alcohol or opioids.[2]
There have been several fatal overdoses in which rilmazolam was identified as the primary causative agent or a major contributing factor.[2][9][full citation needed]
Legal status
[edit]Rilmazolam itself is not approved for medical use in any country, but rilmazafone is approved in Japan under the brand name Rhythmy for the treatment of insomnia at a dose of 1-2mg once daily, and as a pre-anesthetic medication (2 mg before surgery).[2] In Japan, rilmazafone is classified as a prescription medication.
See also
[edit]- Flutazolam (Coreminal), discontinued January 2025
- Etizolam
- Phenazepam
- Mexazolam (Melex), discontinued July 2025
- Flutoprazepam (Restas), discontinued[when?]
- Prazepam
- Triazolam
References
[edit]- ^ a b Koike M, Norikura R, Sugeno K (March 1986). "Intestinal activation of a new sleep inducer 450191-S, a 1H-1,2,4-triazolyl benzophenone derivative, in rats". Journal of Pharmacobio-Dynamics. 9 (3): 315–320. doi:10.1248/bpb1978.9.315. PMID 3454653.
- ^ a b c d "Rilmazolam".
{{cite web}}:|access-date=requires|url=(help); Missing or empty|url=(help) - ^ a b "Rilmazolam". MedChemExpress. Retrieved 2026-06-22.
- ^ a b "Rilmazolam (CAS 50330-59-1)". Cayman Chemical. Retrieved 2026-06-22.
- ^ "rilmazolam (Q98113711)". Wikidata. Retrieved 2026-06-22.
- ^ "Rilmazolam & Rilmazafone – Scientific Insight into Designer Benzodiazepines in European Research". SlideServe. Retrieved 2026-06-22.
- ^ Yamaguchi T, et al. (1987). "Metabolites of 450191-S in human plasma and urine". Journal of Pharmacobio-Dynamics. 10.
- ^ "N-Desmethyl Rilmazolam". MedChemExpress. Retrieved 2026-06-22.
- ^ "Rilmazafone: A designer benzodiazepine pro-drug involved in fatal intoxications". 2023.
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