Chemistry:Rilmazolam
Rilmazolam is a triazolobenzodiazepine and the principal active metabolite of rilmazafone, a prodrug sold under the brand name Rhythmy (リスミー) in Japan and approved there for the treatment of insomnia and as a pre-anesthetic agent.[1] Rilmazolam itself has never been independently developed or approved for medical use in any country.
Chemical and physical data
Rilmazolam is a triazolobenzodiazepine in which a triazole ring is fused to the benzodiazepine diazepine core. Its molecular formula is C19H15Cl2N5O and its molecular weight is 400.26 g/mol.[2][3] Its IUPAC name is 8-chloro-6-(2-chlorophenyl)-N,N-dimethyl-4H-[1,2,4]triazolo[1,5-a][1,4]benzodiazepine-2-carboxamide. It is soluble in methanol and chloroform.[3]
Pharmacology
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 the benzodiazepine class.[2]
Metabolism and pharmacokinetics
Rilmazolam is not administered directly but is formed in vivo from rilmazafone, its prodrug, which has negligible affinity for benzodiazepine receptors. After oral administration of rilmazafone, aminopeptidase enzymes in the small intestine cleave the parent compound to a desglycylated intermediate (191DG), which then undergoes spontaneous non-enzymatic cyclization to yield rilmazolam. This activation occurs during a single passage through the intestinal wall, such that rilmazafone itself is not detectable in human plasma after therapeutic doses of 1–2 mg.[1]
Oral rilmazafone produces at least five active metabolites in humans: rilmazolam (M-1), M-2, M-A, and M-3, with M-4 being the predominant species in human plasma for up to six hours after dosing — a pattern distinct from that seen in animal studies. Urinary excretion accounts for the bulk of elimination, with 44–68% of the administered dose recovered in urine within 24 hours, primarily as M-4. Other metabolites and their conjugates account for less than 1% of the dose.[4] Rilmazolam is further metabolized to N-desmethylrilmazolam, which is also pharmacologically active.[5]
Toxicology
Rilmazolam can cause dose-dependent central nervous system depression, including sedation, impaired motor coordination, anterograde amnesia, and next-day residual effects. Overdose may lead to respiratory depression, coma, and death, particularly in combination with other CNS depressants such as ethanol or opioids. Several fatal overdoses have been reported in which rilmazolam was identified as the primary causative agent or a major contributing factor.[6]
References
- ↑ 1.0 1.1 "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. March 1986. doi:10.1248/bpb1978.9.315. PMID 3454653.
- ↑ 2.0 2.1 "Rilmazolam". MedChemExpress. https://www.medchemexpress.eu/rilmazolam.html.
- ↑ 3.0 3.1 "Rilmazolam (CAS 50330-59-1)". Cayman Chemical. https://www.caymanchem.com/product/39863/rilmazolam.
- ↑ "Metabolites of 450191-S in human plasma and urine". Journal of Pharmacobio-Dynamics 10. 1987. PMID 2886322.
- ↑ "N-Desmethyl Rilmazolam". MedChemExpress. https://www.medchemexpress.com.
- ↑ "Rilmazafone: A designer benzodiazepine pro-drug involved in fatal intoxications". Journal of Analytical Toxicology 47 (7): 640–643. 15 September 2023. doi:10.1093/jat/bkad041. PMID 37348041.
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