Bretazenil

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Bretazenil
Bretazenil.svg
Clinical data
ATC code
  • none
Pharmacokinetic data
Elimination half-life 2.5 hours
Identifiers
  • tert-butyl-8-bromo-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo(1,5-a)-pyrrolo(2,1-c)(1,4)benzodiazepine-1-carboxylate
CAS Number
PubChem CID
IUPHAR/BPS
ChemSpider
UNII
ChEMBL
CompTox Dashboard (EPA)
Chemical and physical data
Formula C19H20BrN3O3
Molar mass 418.291 g·mol−1
3D model (JSmol)
  • O=C(OC(C)(C)C)c1ncn2c4c(C(=O)N3[C@H](c12)CCC3)c(Br)ccc4
  • InChI=1S/C19H20BrN3O3/c1-19(2,3)26-18(25)15-16-13-8-5-9-22(13)17(24)14-11(20)6-4-7-12(14)23(16)10-21-15/h4,6-7,10,13H,5,8-9H2,1-3H3/t13-/m0/s1 Yes check.svgY
  • Key:LWUDDYHYYNNIQI-ZDUSSCGKSA-N Yes check.svgY
   (verify)

Bretazenil (Ro16-6028) is an imidazopyrrolobenzodiazepine [1] anxiolytic drug which is derived from the benzodiazepine family, and was invented in 1988. It is most closely related in structure to the GABA antagonist flumazenil, although its effects are somewhat different. It is classified as a high-potency benzodiazepine due to its high affinity binding to benzodiazepine binding sites [2] [3] where it acts as a partial agonist. [4] Its profile as a partial agonist and preclinical trial data suggests that it may have a reduced adverse effect profile. [5] In particular bretazenil has been proposed to cause a less strong development of tolerance and withdrawal syndrome. [6] Bretazenil differs from traditional 1,4-benzodiazepines by being a partial agonist and because it binds to α1, α2, α3, α4, α5 and α6 subunit containing GABAA receptor benzodiazepine receptor complexes. 1,4-benzodiazepines bind only to α1, α2, α3 and α5 GABAA benzodiazepine receptor complexes. [1]

Contents

History

Bretazenil was originally developed as an anti-anxiety drug and has been studied for its use as an anticonvulsant [7] [8] but has never commercialised. It is a partial agonist for GABAA receptors in the brain. David Nutt from the University of Bristol has suggested bretazenil as a possible base from which to make a better social drug, as it displays several of the positive effects of alcohol intoxication such as relaxation and sociability, but without the bad effects such as aggression, amnesia, nausea, loss of coordination, liver disease and brain damage. The effects of bretazenil can also be quickly reversed by the action of flumazenil, which is used as an antidote to benzodiazepine overdose, [9] in contrast to alcohol for which there is no effective and reliable antidote.[ citation needed ]

Traditional benzodiazepines are associated with side effects such as drowsiness, physical dependence and abuse potential. It was hoped that bretazenil and other partial agonists would be an improvement on traditional benzodiazepines which are full agonists due to preclinical evidence that their side effect profile was less than that of full agonist benzodiazepines. For a variety of reasons however, bretazenil and other partial agonists such as pazinaclone and abecarnil were not clinically successful. However, research continues into other compounds with partial agonist and compounds which are selective for certain GABAA benzodiazepine receptor subtypes. [10]

Tolerance and dependence

In a study in rats, cross-tolerance between the benzodiazepine drug chlordiazepoxide and bretazenil has been demonstrated. [11] In a primate study bretazenil was found to be able to replace the full agonist diazepam in diazepam dependent primates without precipitating withdrawal effects, demonstrating cross tolerance between bretazenil and benzodiazepine agonists, whereas other partial agonists precipitated a withdrawal syndrome. The differences are likely due to differences in instrinsic properties between different benzodiazepine partial agonists. [12] Cross-tolerance has also been shown between bretazenil and full agonist benzodiazepines in rats. [13] In rats tolerance is slower to develop to the anticonvulsant effects compared to the benzodiazepine site full agonist diazepam. However, tolerance developed to the anticonvulsant effects of bretazenil partial agonist more quickly than they developed to imidazenil. [14]

Pharmacology

Bretazenil has a more broad spectrum of action than traditional benzodiazepines as it has been shown to have low affinity binding to α4 and α6 GABAA receptors in addition to acting on α1, α2, α3 and α5 subunits which traditional benzodiazepine drugs work on. The partial agonist imidazenil does not, however, act at these subunits. [15] [16] [17] 0.5mg of bretazenil is approximately equivalent in its psychomotor-impairing effect to 10 mg of diazepam. Bretazenil produces marked sedative-hypnotic effects when taken alone and when combined with alcohol. This human study also indicates that bretazenil is possibly more sedative than diazepam. The reason is unknown, but the study suggests the possibility that a full-agonist metabolite may be generated in humans but not animals previously tested or else that there are significant differences in benzodiazepine receptor population in animals and humans. [18]

In a study of monkeys bretazenil has been found to antagonize the effects of full agonist benzodiazepines. However, bretazenil has been found to enhance the effects of neurosteroids acting on the neurosteroid binding site of the GABAA receptor. [19] Another study found that bretazenil acted as an antagonist provoking withdrawal symptoms in monkeys who were physically dependent on the full agonist benzodiazepine triazolam. [20]

Partial agonists of benzodiazepine receptors have been proposed as a possible alternative to full agonists of the benzodiazepine site to overcome the problems of tolerance, dependence and withdrawal which limits the role of benzodiazepines in the treatment of anxiety, insomnia and epilepsy. Such adverse effects appear to be less problematic with bretazenil than full agonists. [21] Bretazenil has also been found to have less abuse potential than benzodiazepine full agonists such as diazepam and alprazolam, [22] [23] however long-term use of bretazenil would still be expected to result in dependence and addiction.[ citation needed ]

Bretazenil alters the sleep EEG profile and causes a reduction in cortisol secretion and increases significantly the release of prolactin. [24] Bretazenil has effective hypnotic properties but impairs cognitive ability in humans. Bretazenil causes a reduction in the number of movements between sleep stages and delays movement into REM sleep. At a dosage of 0.5 mg of bretazenil REM sleep is decreased and stage 2 sleep is lengthened. [25]

See also

Related Research Articles

<span class="mw-page-title-main">Benzodiazepine</span> Class of depressant drugs

Benzodiazepines, colloquially called "benzos", are a class of depressant drugs whose core chemical structure is the fusion of a benzene ring and a diazepine ring. They are prescribed to treat conditions such as anxiety disorders, insomnia, and seizures. The first benzodiazepine, chlordiazepoxide (Librium), was discovered accidentally by Leo Sternbach in 1955 and was made available in 1960 by Hoffmann–La Roche, who soon followed with diazepam (Valium) in 1963. By 1977, benzodiazepines were the most prescribed medications globally; the introduction of selective serotonin reuptake inhibitors (SSRIs), among other factors, decreased rates of prescription, but they remain frequently used worldwide.

<span class="mw-page-title-main">Diazepam</span> Benzodiazepine sedative

Diazepam, first marketed as Valium, is a medicine of the benzodiazepine family that acts as an anxiolytic. It is commonly used to treat a range of conditions, including anxiety, seizures, alcohol withdrawal syndrome, muscle spasms, insomnia, and restless legs syndrome. It may also be used to cause memory loss during certain medical procedures. It can be taken orally, as a suppository inserted into the rectum, intramuscularly, intravenously or used as a nasal spray. When injected intravenously, effects begin in one to five minutes and last up to an hour. Orally, effects begin after 15 to 60 minutes.

<span class="mw-page-title-main">Zolpidem</span> Hypnotic medication

Zolpidem, sold under the brand name Ambien among others, is a medication primarily used for the short-term treatment of sleeping problems. Guidelines recommend that it be used only after cognitive behavioral therapy for insomnia and behavioral changes, such as sleep hygiene, have been tried. It decreases the time to sleep onset by about fifteen minutes and at larger doses helps people stay asleep longer. It is taken by mouth and is available in conventional tablets, sublingual tablets, or oral spray.

<span class="mw-page-title-main">Nordazepam</span> Benzodiazepine derivative medication

Nordazepam is a 1,4-benzodiazepine derivative. Like other benzodiazepine derivatives, it has amnesic, anticonvulsant, anxiolytic, muscle relaxant, and sedative properties. However, it is used primarily in the treatment of anxiety disorders. It is an active metabolite of diazepam, chlordiazepoxide, clorazepate, prazepam, pinazepam, and medazepam.

<span class="mw-page-title-main">Clorazepate</span> Benzodiazepine medication

Clorazepate, sold under the brand name Tranxene among others, is a benzodiazepine medication. It possesses anxiolytic, anticonvulsant, sedative, hypnotic, and skeletal muscle relaxant properties. Clorazepate is an unusually long-lasting benzodiazepine and serves as a prodrug for the equally long-lasting desmethyldiazepam, which is rapidly produced as an active metabolite. Desmethyldiazepam is responsible for most of the therapeutic effects of clorazepate.

<span class="mw-page-title-main">Alpidem</span> Anxiolytic medication

Alpidem, sold under the brand name Ananxyl, is a nonbenzodiazepine anxiolytic medication which was briefly used to treat anxiety disorders but is no longer marketed. It was previously marketed in France, but was discontinued due to liver toxicity. Alpidem is taken by mouth.

<span class="mw-page-title-main">Pagoclone</span> Chemical compound

Pagoclone is an anxiolytic agent from the cyclopyrrolone family, related to better-known drugs such as the sleeping medication zopiclone. It was synthesized by a French team working for Rhone-Poulenc & Rorer S.A. Pagoclone belongs to the class of nonbenzodiazepines, which have similar effects to the older benzodiazepine group, but with quite different chemical structures. It was never commercialised.

<span class="mw-page-title-main">Chlordiazepoxide</span> Benzodiazepine class sedative and hypnotic medication

Chlordiazepoxide, trade name Librium among others, is a sedative and hypnotic medication of the benzodiazepine class; it is used to treat anxiety, insomnia and symptoms of withdrawal from alcohol and other drugs.

<span class="mw-page-title-main">Benzodiazepine withdrawal syndrome</span> Signs and symptoms due to benzodiazepines discontinuation in physically dependent persons

Benzodiazepine withdrawal syndrome is the cluster of signs and symptoms that may emerge when a person who has been taking benzodiazepines as prescribed develops a physical dependence on them and then reduces the dose or stops taking them without a safe taper schedule.

<span class="mw-page-title-main">Imidazenil</span> Chemical compound

Imidazenil is an experimental anxiolytic drug which is derived from the benzodiazepine family, and is most closely related to other imidazobenzodiazepines such as midazolam, flumazenil, and bretazenil.

<span class="mw-page-title-main">QH-II-66</span> Sedative drug

QH-II-66 (QH-ii-066) is a sedative drug which is a benzodiazepine derivative. It produces some of the same effects as other benzodiazepines, but is much more selective than most other drugs of this class and so produces somewhat less sedation and ataxia than other related drugs such as diazepam and triazolam, although it still retains anticonvulsant effects.

<span class="mw-page-title-main">Abecarnil</span> Chemical compound

Abecarnil (ZK-112,119) is an anxiolytic drug from the β-Carboline family. It is one of a relatively recently developed class of medicines known as the nonbenzodiazepines, which have similar effects to the older benzodiazepine group, but with quite different chemical structures. It is a partial agonist acting selectively at the benzodiazepine site of the GABAA receptor.

<span class="mw-page-title-main">Pipequaline</span> Chemical compound

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<span class="mw-page-title-main">L-838,417</span> Chemical compound

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<span class="mw-page-title-main">SL651498</span> Chemical compound

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<span class="mw-page-title-main">ELB-139</span> Chemical compound

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<span class="mw-page-title-main">TPA-023</span> Chemical compound

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<span class="mw-page-title-main">Benzodiazepine dependence</span> Medical condition

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<span class="mw-page-title-main">ZK-93423</span> Chemical compound

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<span class="mw-page-title-main">Divaplon</span> Chemical compound

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References

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  2. ↑ Giusti P, Guidetti G, Costa E, Guidotti A (June 1991). "The preferential antagonism of pentylenetetrazole proconflict responses differentiates a class of anxiolytic benzodiazepines with potential antipanic action". The Journal of Pharmacology and Experimental Therapeutics. 257 (3): 1062–8. PMID   1675286.
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  11. ↑ Bronson ME (1993). "Tolerance/cross-tolerance to the discriminative stimulus effects of chlordiazepoxide and bretazenil". Molecular and Chemical Neuropathology. 18 (1–2): 85–98. doi:10.1007/BF03160023. PMID   8385466.
  12. ↑ Martin JR, Jenck F, Moreau JL (October 1995). "Comparison of benzodiazepine receptor ligands with partial agonistic, antagonistic or partial inverse agonistic properties in precipitating withdrawal in squirrel monkeys". The Journal of Pharmacology and Experimental Therapeutics. 275 (1): 405–11. PMID   7562578.
  13. ↑ Bronson ME (Jun–Jul 1995). "Chronic bretazenil produces tolerance to chlordiazepoxide, midazolam, and abecarnil". Pharmacology, Biochemistry, and Behavior. 51 (2–3): 481–90. doi:10.1016/0091-3057(95)00014-N. PMID   7667373. S2CID   26419284.
  14. ↑ Auta J, Giusti P, Guidotti A, Costa E (September 1994). "Imidazenil, a partial positive allosteric modulator of GABAA receptors, exhibits low tolerance and dependence liabilities in the rat". The Journal of Pharmacology and Experimental Therapeutics. 270 (3): 1262–9. PMID   7932179.
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  19. ↑ McMahon LR, France CP (February 2006). "Differential behavioral effects of low efficacy positive GABAA modulators in combination with benzodiazepines and a neuroactive steroid in rhesus monkeys". British Journal of Pharmacology. 147 (3): 260–8. doi:10.1038/sj.bjp.0706550. PMC   1751295 . PMID   16331290.
  20. ↑ Weerts EM, Ator NA, Kaminski BJ, Griffiths RR (September 2005). "Comparison of the behavioral effects of bretazenil and flumazenil in triazolam-dependent and non-dependent baboons". European Journal of Pharmacology. 519 (1–2): 103–13. doi:10.1016/j.ejphar.2005.06.038. PMID   16129429.
  21. ↑ Schoch P, Moreau JL, Martin JR, Haefely WE (1993). "Aspects of benzodiazepine receptor structure and function with relevance to drug tolerance and dependence". Biochemical Society Symposium. 59: 121–34. PMID   7910739.
  22. ↑ Busto U, Kaplan HL, Zawertailo L, Sellers EM (April 1994). "Pharmacologic effects and abuse liability of bretazenil, diazepam, and alprazolam in humans". Clinical Pharmacology and Therapeutics. 55 (4): 451–63. doi:10.1038/clpt.1994.55. PMID   8162672. S2CID   21357076.
  23. ↑ Sellers EM, Kaplan HL, Busto UE, et al. (1992). "Abuse liability of bretazenil and other partial agonists". Clinical Neuropharmacology. 15 Suppl 1 Pt A: 409A. doi:10.1097/00002826-199201001-00213. PMID   1354047. S2CID   40095405.
  24. ↑ Guldner J, Trachsel L, Kratschmayr C, Rothe B, Holsboer F, Steiger A (November 1995). "Bretazenil modulates sleep EEG and nocturnal hormone secretion in normal men". Psychopharmacology. 122 (2): 115–21. doi:10.1007/BF02246085. PMID   8848526. S2CID   34247989.
  25. ↑ Gieschke R, Cluydts R, Dingemanse J, De Roeck J, De Cock W (November 1994). "Effects of bretazenil vs. zolpidem and placebo on experimentally induced sleep disturbance in healthy volunteers". Methods and Findings in Experimental and Clinical Pharmacology. 16 (9): 667–75. PMID   7746029.
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