Bretazenil (Ro16-6028) is an imidazopyrrolobenzodiazepine[1]anxiolytic drug which is derived from thebenzodiazepine family, and was invented in 1988. It is most closely related in structure to the GABA antagonistflumazenil, 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 apartial 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 oftolerance andwithdrawal 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 α5GABAA benzodiazepine receptor complexes.[1]
Bretazenil was originally developed as an anti-anxiety drug and has been studied for its use as an anticonvulsant[7][8] but has never been commercialised. It is apartial agonist for the benzodiazepine site of theGABAAreceptors in the brain.David Nutt from theUniversity 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 ofalcohol 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 offlumazenil, which is used as an antidote tobenzodiazepine overdose,[9] in contrast to alcohol for which there is no effective and reliableantidote.[citation needed]
Traditional benzodiazepines are associated with side effects such as drowsiness,physical dependence andabuse 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 aspazinaclone andabecarnil were not clinically successful.[why?] However, research continues into other compounds with partial agonist and compounds which are selective for certain GABAA benzodiazepine receptor subtypes.[10]
In a study in rats,cross-tolerance between the benzodiazepine drugchlordiazepoxide and bretazenil has been demonstrated.[11] In aprimate study bretazenil was found to be able to replace the full agonistdiazepam in diazepam dependent primates without precipitating withdrawal effects, demonstratingcross 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 toimidazenil.[14]
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 agonistimidazenil 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 ofneurosteroids 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 werephysically dependent on the full agonist benzodiazepinetriazolam.[20]
Partial agonists of benzodiazepine receptors have been proposed as a possible alternative to full agonists of the benzodiazepine site to overcome the problems oftolerance,dependence andwithdrawal which limits the role of benzodiazepines in the treatment ofanxiety,insomnia andepilepsy. 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 asdiazepam andalprazolam,[22][23] however long-term use of bretazenil would still be expected to result in dependence and addiction.[citation needed]
Bretazenil alters the sleepEEG profile and causes a reduction incortisol secretion and increases significantly the release ofprolactin.[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 intoREM sleep. At a dosage of 0.5 mg of bretazenil REM sleep is decreased and stage 2 sleep is lengthened.[25]
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^Finn DA, Gee KW (November 1993). "A comparison of Ro 16-6028 with benzodiazepine receptor 'full agonists' on GABAA receptor function".European Journal of Pharmacology.247 (3):233–7.doi:10.1016/0922-4106(93)90190-K.PMID7905829.
^Haefely W, Facklam M, Schoch P, Martin JR, Bonetti EP, Moreau JL, et al. (1992). "Partial agonists of benzodiazepine receptors for the treatment of epilepsy, sleep, and anxiety disorders".Advances in Biochemical Psychopharmacology.47:379–94.PMID1324584.
^Kunovac JL, Stahl SM (December 1995). "Future directions in anxiolytic pharmacotherapy".The Psychiatric Clinics of North America.18 (4):895–909.doi:10.1016/S0193-953X(18)30030-3.PMID8748388.
^Płaźnik A (1995). "Pharmacology of tolerance to benzodiazepine receptor ligands".Polish Journal of Pharmacology.47 (6):489–99.PMID8868371.
^Cole JC, Rodgers RJ (December 1993). "An ethological analysis of the effects of chlordiazepoxide and bretazenil (Ro 16-6028) in the murine elevated plus-maze".Behavioural Pharmacology.4 (6):573–580.doi:10.1097/00008877-199312000-00003.PMID11224226.
^Brabcová R, Kubová H, Velísek L, Mares P (1993). "Effects of a benzodiazepine, bretazenil (Ro 16-6028), on rhythmic metrazol EEG activity: comparison with standard anticonvulsants".Epilepsia.34 (6):1135–40.doi:10.1111/j.1528-1157.1993.tb02146.x.PMID8243369.S2CID24157328.
^Atack JR (May 2005). "The benzodiazepine binding site of GABA(A) receptors as a target for the development of novel anxiolytics".Expert Opinion on Investigational Drugs.14 (5):601–18.doi:10.1517/13543784.14.5.601.PMID15926867.S2CID22793644.
^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.PMID8385466.
^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.doi:10.1016/S0022-3565(25)12064-8.PMID7562578.
^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.PMID7667373.S2CID26419284.
^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.doi:10.1016/S0022-3565(25)22535-6.PMID7932179.
^Witkin JM, Acri JB, Gleeson S, Barrett JE (January 1997). "Blockade of behavioral effects of bretazenil by flumazenil and ZK 93,426 in pigeons".Pharmacology, Biochemistry, and Behavior.56 (1):1–7.doi:10.1016/S0091-3057(96)00120-7.PMID8981602.S2CID36088521.
^Knoflach F, Benke D, Wang Y, Scheurer L, Lüddens H, Hamilton BJ, et al. (November 1996). "Pharmacological modulation of the diazepam-insensitive recombinant gamma-aminobutyric acidA receptors alpha 4 beta 2 gamma 2 and alpha 6 beta 2 gamma 2".Molecular Pharmacology.50 (5):1253–61.doi:10.1016/S0026-895X(25)09554-9.PMID8913357.
^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.PMID16129429.
^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.PMID7910739.
^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.PMID8162672.S2CID21357076.
^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.PMID8848526.S2CID34247989.
^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.PMID7746029.
