User:Kgoldynia/sandbox

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Kgoldynia/sandbox
Clinical data
ATC code
  • none
Identifiers
  • (3S)-5-(2-Chlorophenyl)-3-methyl-7-nitro-1,3-dihydro-2H-1,4-benzodiazepin-2-one
CAS Number
PubChem CID
ChemSpider
UNII
ChEMBL
Chemical and physical data
FormulaC16H12ClN3O3
Molar mass329.74 g·mol−1
3D model (JSmol)
  • O=N(C1=CC2=C(NC([C@H](C)N=C2C3=CC=CC=C3)=O)C=C1)=O
  • InChI=1S/C16H12ClN3O3/c1-9-16(21)19-14-7-6-10(20(22)23)8-12(14)15(18-9)11-4-2-3-5-13(11)17/h2-9H,1H3,(H,19,21)/t9-/m0/s1 checkY
  • Key:LMUVYJCAFWGNSY-VIFPVBQESA-N checkY
 ☒NcheckY (what is this?)  (verify)


Meclonazepam[edit]

Meclonazepam is an anxiolytic, benzodiazepine derivative drug. [1] It has been shown that, when administered at high doses, it can act as an effective therapeutic and prophylactic treatment of schistosomiasis.[2] Meclonazepam has been proposed as a new schistosomicidal drug due to its effectiveness against S. mansoni and S. haematobium trematode worms, however it has been proven to have a low level of selectivity, casting doubt on whether it is the best drug to treatment schistosomiasis. [2] Meclonazepam is not FDA approved in the US.

History[edit]

Meclonazepam,[3] was discovered by a team at Hoffmann-La Roche in the 1970s.[4] It was developed due to parasite resistance to Preziquantel, the only available drug to treat schistosomiasis at the time.[5] [6] A key factor that led to researchers’ interest in Meclonazepam as a schistomicidal drug treatment was its structural similarity to the drug clonazepam,[4] a benzodiazepine derivative that had already been shown to have both antiepileptic and anxiolytic effects.[7]

Mechanism of Action[edit]

There is uncertainty about the exact mechanism of action of meclonazepam, but two benzodiazepine-binding sites have been identified as possible drug targets. [8] [9]

Pharmacological Properties[edit]

Various studies of S. mansoni have identified some of the pharmacological properties of meclonazepam. Findings of these studies have shown that meclonazepam has a low affinity binding site and a Kd of 2 µM, [10] [2] as well as a half maximal lethal concentration (LC50) of 3 µM, which suggest that administration of meclonazepam leads to parasite death through calcium dependent paralysis and tegumental dysfunction. [11] [12] [13] [2] The Cmax of meclonazepam has been found to be less than 600 nM. This indicates that when administered in vivo, meclonazepam likely acts at unidentified receptors, as this concentration is less than that which would be effective on schistosomes in culture. [2]

Both meclonazepam and clonazepam show an inversely proportional relationship between the proportion of the drug in blood plasma and the dose of the drug, showing that their structural similarities lead to pharmacological similarities. [14] [15] [16]

Chemical Properties and Adverse Effects[edit]

Molecular modeling has been used to determine the structure and chemical properties of meclonazepam. The chemical structure contains a 1,4-diazepine ring in an equatorial position, which minimizes the steric hindrance of amide and imine moieties present on the compound.[17] A key structural aspect that leads to schistosomicidal effect of the drug is the amide moiety of the M conformation of S-(+)-meclonazepam, as it is also found in R-(-)-praquantel, which elicits the same schistosomicidal effect.[17] In addition to its therapeutic effects, meclonazepam shares the same adverse effects as other benzodiazepines such drowsiness, ataxia and muscle weakness. [18] [19] These side effects can be overcome, however, when it is administered in conjunction with the drug Ro 15-1788. [19]

Research[edit]

Biological assays[edit]

Meclonazepam has been studied, along with praziquantel and clonazepam, in relation to short-term worm motility. The application of each of these drugs paralyzed spastic movements in worms.[17]


Binding assay[edit]

When evaluated through a binding assay, meclonazepam showed less of an affinity for both central and peripheral benzodiazepine binding sites relative to other ligands. [5]


Schistosomicidal effect[edit]

An in vitro study in parasitic worms showed meclonazepam to have therapeutic effects against schistosomaisis. A 5-day exposure to the drug resulted in the death of all of the worms exposed. [18]

Dosing studies[edit]

Central arousal, mood and psychomotor performance were all evaluate after single oral doses of meclonazepam were administered. Doses greater than 1 mg elicited impairments in all three areas. With a dose of 4 mg, these impairments were most prominent in the first three hours, but lasted for up to 6 hours.[20]

References[edit]

  1. ^ Ansseau M, Doumont A, Thiry D, von Frenckell R, Collard J (1985). Initial study of methylclonazepam in generalized anxiety disorder. Evidence for greater power in the cross-over design. Psychoparmacology 87:130–135
  2. ^ a b c d e Dufour V, Beech RN, Wever C, Dent JA, Geary TG (2013). Molecular Cloning and Characterization of Novel Glutamate-Gated Chloride Channel Subunits from Schistosoma mansoni. PLoS Pathog 9(8): e1003586
  3. ^ U.S. Patent 4,031,078
  4. ^ a b The Lundbeck Institute. "Meclonazepam". Psychotropics. Lundbeck.
  5. ^ a b Thibaut, J.; Monteiro, L.; Leite, L. et al. (2009). "The effects of 3-methylclonazepam on Schistosoma mansoni musculature are not mediated by benzodiazepine receptors". European Journal of Pharmacology 606: 9–16.
  6. ^ Doenhoff M.J., Cioli D., Utzinger J. (2008). Praziquantel: mechanisms of action, resistance and new derivatives for schistosomiasis. Cur Op Inf Dis 21:659–667.
  7. ^ Hotez P.J., Kamath A. (2009). Neglected tropical diseases in Sub- Saharan Africa: review of their prevalence, distribution, and dis- ease burden. PLoS Negl Trop Dis 3:e412.
  8. ^ Noël F, Mendonça-Silva DL, Thibaut JP, Lopes DV (2007). Characterization of two classes of benzodiazepine binding sites in Schistosoma mansoni. Parasitology 134:1003–1012.
  9. ^ Abdul-Ghani, R. A.; Loutfy, N.; Hassan, A. (2009). "Experimentally promising antischistosomal drugs: A review of some drug candidates not reaching the clinical use". Parasitology Research 105 (4): 899–906.
  10. ^ Bennett JL (1980). Characteristics of antischistosomal benzodiazepine binding sites in Schistosoma mansoni. J Parasitol 66: 742–747.
  11. ^ Pax R, Bennett JL, Fetterer R (1978). A benzodiazepine derivative and praziquantel: effects on musculature of Schistosoma mansoni and Schistosoma japonicum. Naunyn Schmiedebergs Arch Pharmacol 304: 309–315.
  12. ^ Forget E, Félix H, Notteghem MJ, Léger N (1982). Appréciation de l'activité de dérivés schistosomicides en microscopie électronique. Bull Soc Pathol Exot Filiales 75: 192–200.
  13. ^ Bricker CS, Depenbusch JW, Bennett JL, Thompson DP (1983). The relationship between tegumental disruption and muscle contraction Schistosoma mansoni exposed to various compounds. Z Parasitenkd 69: 61–71.
  14. ^ Berlin A, Dahlström H (1975). Pharmacokinetics of the anticonvulsant drug clonazepam evaluated from single oral and intravenous doses and by repeated oral administration. Eur J Clin Pharmacol 9: 155–159.
  15. ^ Crevoisier C, Delisle MC, Joseph I, Foletti G (2003). Comparative single-dose pharmacokinetics of clonazepam following intravenous, intramuscular and oral administration to healthy volunteers. Eur Neurol 49: 173–177.
  16. ^ Coassolo P, Aubert C, Cano J-P (1985). Plasma determination of 3-methylclonazepam by capillary gas chromatography. J Chromatogr 338: 347–355.
  17. ^ a b c Carla M". S. Menezes. (2012). "Synthesis, Biological Evaluation, and Structure–activity Relationship of Clonazepam, Meclonazepam, and 1,4-Benzodiazepine Compounds with Schistosomicidal Activity. Chem Biol Drug Des 79: 943–949
  18. ^ a b <Mahajan, A.; Kumar, V.; Nuha, R. N. et al. (2008). "Meclonazepam analogues as potential new antihelmintic agents". Bioorganic & Medicinal Chemistry Letters 18: 2333–2336.
  19. ^ a b Darragh, A.; Lambe, R.; O’Boyle C. (1982). "Antagonism of central effects of 3-methylclonazepam". Br J Clin Pharmacol 14 (6): 171–2.
  20. ^ O'Boyle, C.; Lambe, R.; Darragh A. (1985). "Central effects in man of the novel schistosomicidal benzodiazepine meclonazepam". European Journal of Clinical Pharmacology 29 (1): 105–108.
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