Bretazenil
Encyclopedia
Bretazenil is an imidazopyrrolobenzodiazepine anxiolytic
drug which is derived from the benzodiazepine
family, and was invented in 1988. It is most closely related in structure to the benzodiazepine antagonist flumazenil
, although its effects are somewhat different. It is classed as a high-potency benzodiazepine due to its high affinity binding to benzodiazepine binding sites where it acts as a partial agonist
. Its profile as a partial agonist and preclinical trial data suggests that it may have a reduced adverse effect profile. In particular bretazenil has been proposed to cause a less strong development of tolerance and withdrawal
syndrome. Bretazenil differs from traditional 1,4 benzodiazepines by being a partial agonist and because it binds to alpha,1, 2, 3, 4, 5 and 6 subunit containing GABAA benzodiazepine receptor complexes. 1,4 benzodiazepines bind only to alpha 1, 2, 3 and 5 GABAA benzodiazepine receptor complexes.
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
, in contrast to alcohol for which there is no effective and reliable antidote
.
Traditional benzodiazepines are associated with side effects such as drowsiness, physical dependence
and abuse
potential and have become increasingly unpopular in the general publics eyes. 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.
between the benzodiazepine drug chlordiazepoxide
and bretazenil has been demonstrated. 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. Cross-tolerance has also been shown between bretazenil and full agonist benzodiazepines in rats. 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
.
does not, however, act at these subunits. The approximate equivalent dose of bretazenil is 0.5 mg of bretazenil is equivalent to 10 mg of diazepam. The elimination half-life of bretazenil is 2.5 hours and is rapidly absorbed after oral administration. Contrary to the results found in animals, no indications for a dissociation of the sedative and anxiolytic effects of bretazenil were found in man. In fact. bretazenil has a more pronounced psychomotor-impairing effect than 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.
In a study of monkeys bretazenil has been found to antagonise 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. Another study found that bretazenil acted as an antagonist provoking withdrawal symptoms in monkeys who were physically dependent on the full agonist benzodiazepine triazolam
.
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. Bretazenil, also has been found to have less abuse potential than benzodiazepine full agonists such as diazepam
and alprazolam
, long-term use of bretazenil would still be expected to result in dependence and addiction.
Bretazenil alters the sleep EEG
profile and causes a reduction in cortisol
secretion and increases significantly the release of prolactin
. 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.
The use of an isocyanide
can be seen.
Anxiolytic
An anxiolytic is a drug used for the treatment of anxiety, and its related psychological and physical symptoms...
drug which is derived from the benzodiazepine
Benzodiazepine
A benzodiazepine is a psychoactive drug whose core chemical structure is the fusion of a benzene ring and a diazepine ring...
family, and was invented in 1988. It is most closely related in structure to the benzodiazepine antagonist flumazenil
Flumazenil
Flumazenil is a benzodiazepine antagonist available for injection only, and the only benzodiazepine receptor antagonist on the market today.It was first introduced in 1987 by Hoffmann-La Roche under the trade name Anexate, but only approved by...
, although its effects are somewhat different. It is classed as a high-potency benzodiazepine due to its high affinity binding to benzodiazepine binding sites where it acts as a partial agonist
Partial agonist
Partial agonists bind and activate a given receptor, but have only partial efficacy at the receptor relative to a full agonist...
. Its profile as a partial agonist and preclinical trial data suggests that it may have a reduced adverse effect profile. In particular bretazenil has been proposed to cause a less strong development of tolerance and withdrawal
Withdrawal
Withdrawal can refer to any sort of separation, but is most commonly used to describe the group of symptoms that occurs upon the abrupt discontinuation/separation or a decrease in dosage of the intake of medications, recreational drugs, and alcohol...
syndrome. Bretazenil differs from traditional 1,4 benzodiazepines by being a partial agonist and because it binds to alpha,1, 2, 3, 4, 5 and 6 subunit containing GABAA benzodiazepine receptor complexes. 1,4 benzodiazepines bind only to alpha 1, 2, 3 and 5 GABAA benzodiazepine receptor complexes.
History
Bretazenil was originally developed as an anti-anxiety drug and has been studied for its use as an anticonvulsant but has never commercialised. It is a partial agonistPartial agonist
Partial agonists bind and activate a given receptor, but have only partial efficacy at the receptor relative to a full agonist...
for GABAA
GABA A receptor
The GABAA receptor is an ionotropic receptor and ligand-gated ion channel. Its endogenous ligand is γ-aminobutyric acid , the major inhibitory neurotransmitter in the central nervous system. Upon activation, the GABAA receptor selectively conducts Cl- through its pore, resulting in...
receptors
Receptor (biochemistry)
In biochemistry, a receptor is a molecule found on the surface of a cell, which receives specific chemical signals from neighbouring cells or the wider environment within an organism...
in the brain. David Nutt
David Nutt
David John Nutt is a British psychiatrist and neuropsychopharmacologist specialising in the research of drugs that affect the brain and conditions such as addiction, anxiety and sleep. He was until 2009 a professor at the University of Bristol heading their Psychopharmacology Unit...
from the University of Bristol
University of Bristol
The University of Bristol is a public research university located in Bristol, United Kingdom. One of the so-called "red brick" universities, it received its Royal Charter in 1909, although its predecessor institution, University College, Bristol, had been in existence since 1876.The University is...
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
Alcohol
In chemistry, an alcohol is an organic compound in which the hydroxy functional group is bound to a carbon atom. In particular, this carbon center should be saturated, having single bonds to three other atoms....
intoxication such as relaxation and sociability, but without the bad effects such as aggression, amnesia
Amnesia
Amnesia is a condition in which one's memory is lost. The causes of amnesia have traditionally been divided into categories. Memory appears to be stored in several parts of the limbic system of the brain, and any condition that interferes with the function of this system can cause amnesia...
, nausea
Nausea
Nausea , is a sensation of unease and discomfort in the upper stomach with an involuntary urge to vomit. It often, but not always, precedes vomiting...
, loss of coordination, liver disease and brain damage. The effects of bretazenil can also be quickly reversed by the action of flumazenil
Flumazenil
Flumazenil is a benzodiazepine antagonist available for injection only, and the only benzodiazepine receptor antagonist on the market today.It was first introduced in 1987 by Hoffmann-La Roche under the trade name Anexate, but only approved by...
, which is used as an antidote to benzodiazepine overdose
Benzodiazepine overdose
Benzodiazepine overdose describes the ingestion of one of the drugs in the benzodiazepine class in quantities greater than are recommended or generally practiced. Death as a result of benzodiazepines is uncommon but does occasionally happen. Deaths after hospital admission are considered to be low...
, in contrast to alcohol for which there is no effective and reliable antidote
Antidote
An antidote is a substance which can counteract a form of poisoning. The term ultimately derives from the Greek αντιδιδοναι antididonai, "given against"....
.
Traditional benzodiazepines are associated with side effects such as drowsiness, physical dependence
Physical dependence
Physical dependence refers to a state resulting from chronic use of a drug that has produced tolerance and where negative physical symptoms of withdrawal result from abrupt discontinuation or dosage reduction...
and abuse
Drug abuse
Substance abuse, also known as drug abuse, refers to a maladaptive pattern of use of a substance that is not considered dependent. The term "drug abuse" does not exclude dependency, but is otherwise used in a similar manner in nonmedical contexts...
potential and have become increasingly unpopular in the general publics eyes. 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
Pazinaclone
Pazinaclone is a sedative and anxiolytic drug in the cyclopyrrolone family of drugs. Other cyclopyrrolone drugs include zopiclone and eszopiclone....
and abecarnil
Abecarnil
Abecarnil 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...
were not clinically successful. However, research continues into other compounds with partial agonist and compounds which are selective for certain GABAA benzodiazepine receptor subtypes.
Tolerance and dependence
In a study in rats cross-toleranceCross-tolerance
Cross-tolerance refers to a pharmacological phenomenon, in which a patient being treated with a drug exhibits a physiological resistance to that medication as a result of tolerance to a pharmacologically similar drug. In other words, there is a decrease in response to one drug due to exposure to...
between the benzodiazepine drug chlordiazepoxide
Chlordiazepoxide
Chlordiazepoxide, is a sedative/hypnotic drug and benzodiazepine. It is marketed under the trade names Angirex, Klopoxid, Librax , Libritabs, Librium, Mesural, Multum, Novapam, Risolid, Silibrin, Sonimen and Tropium.Chlordiazepoxide was the first benzodiazepine to be synthesised and...
and bretazenil has been demonstrated. In a primate
Primate
A primate is a mammal of the order Primates , which contains prosimians and simians. Primates arose from ancestors that lived in the trees of tropical forests; many primate characteristics represent adaptations to life in this challenging three-dimensional environment...
study bretazenil was found to be able to replace the full agonist diazepam
Diazepam
Diazepam , first marketed as Valium by Hoffmann-La Roche is a benzodiazepine drug. Diazepam is also marketed in Australia as Antenex. It is commonly used for treating anxiety, insomnia, seizures including status epilepticus, muscle spasms , restless legs syndrome, alcohol withdrawal,...
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. Cross-tolerance has also been shown between bretazenil and full agonist benzodiazepines in rats. 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
Imidazenil
Imidazenil is an anxiolytic drug which is derived from the benzodiazepine family, and is most closely related to other imidazobenzodiazepines such as midazolam, flumazenil and bretazenil....
.
Pharmacology
Bretazenil has a more broad spectrum of action than traditional benzodiazepines as it has been shown to have high affinity binding to alpha 4 and alpha 6 GABAA receptors in addition to acting on alpha1,2,3 and 5 subunits which traditional benzodiazepine drugs work on. The partial agonist imidazenilImidazenil
Imidazenil is an anxiolytic drug which is derived from the benzodiazepine family, and is most closely related to other imidazobenzodiazepines such as midazolam, flumazenil and bretazenil....
does not, however, act at these subunits. The approximate equivalent dose of bretazenil is 0.5 mg of bretazenil is equivalent to 10 mg of diazepam. The elimination half-life of bretazenil is 2.5 hours and is rapidly absorbed after oral administration. Contrary to the results found in animals, no indications for a dissociation of the sedative and anxiolytic effects of bretazenil were found in man. In fact. bretazenil has a more pronounced psychomotor-impairing effect than 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.
In a study of monkeys bretazenil has been found to antagonise 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. Another study found that bretazenil acted as an antagonist provoking withdrawal symptoms in monkeys who were physically dependent on the full agonist benzodiazepine triazolam
Triazolam
Triazolam is a benzodiazepine drug. It possesses pharmacological properties similar to that of other benzodiazepines, but it is generally only used as a sedative to treat severe insomnia...
.
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
Substance dependence
The section about substance dependence in the Diagnostic and Statistical Manual of Mental Disorders does not use the word addiction at all. It explains:...
and withdrawal
Withdrawal
Withdrawal can refer to any sort of separation, but is most commonly used to describe the group of symptoms that occurs upon the abrupt discontinuation/separation or a decrease in dosage of the intake of medications, recreational drugs, and alcohol...
which limits the role of benzodiazepines in the treatment of anxiety
Anxiety
Anxiety is a psychological and physiological state characterized by somatic, emotional, cognitive, and behavioral components. The root meaning of the word anxiety is 'to vex or trouble'; in either presence or absence of psychological stress, anxiety can create feelings of fear, worry, uneasiness,...
, insomnia
Insomnia
Insomnia is most often defined by an individual's report of sleeping difficulties. While the term is sometimes used in sleep literature to describe a disorder demonstrated by polysomnographic evidence of disturbed sleep, insomnia is often defined as a positive response to either of two questions:...
and epilepsy
Epilepsy
Epilepsy is a common chronic neurological disorder characterized by seizures. These seizures are transient signs and/or symptoms of abnormal, excessive or hypersynchronous neuronal activity in the brain.About 50 million people worldwide have epilepsy, and nearly two out of every three new cases...
. Such adverse effects appear to be less problematic with bretazenil than full agonists. Bretazenil, also has been found to have less abuse potential than benzodiazepine full agonists such as diazepam
Diazepam
Diazepam , first marketed as Valium by Hoffmann-La Roche is a benzodiazepine drug. Diazepam is also marketed in Australia as Antenex. It is commonly used for treating anxiety, insomnia, seizures including status epilepticus, muscle spasms , restless legs syndrome, alcohol withdrawal,...
and alprazolam
Alprazolam
Alprazolam is a short-acting anxiolytic of the benzodiazepine class of psychoactive drugs. Alprazolam, like other benzodiazepines, binds to specific sites on the GABAA gamma-amino-butyric acid receptor...
, long-term use of bretazenil would still be expected to result in dependence and addiction.
Bretazenil alters the sleep EEG
EEG
EEG commonly refers to electroencephalography, a measurement of the electrical activity of the brain.EEG may also refer to:* Emperor Entertainment Group, a Hong Kong-based entertainment company...
profile and causes a reduction in cortisol
Cortisol
Cortisol is a steroid hormone, more specifically a glucocorticoid, produced by the adrenal gland. It is released in response to stress and a low level of blood glucocorticoids. Its primary functions are to increase blood sugar through gluconeogenesis; suppress the immune system; and aid in fat,...
secretion and increases significantly the release of prolactin
Prolactin
Prolactin also known as luteotropic hormone is a protein that in humans is encoded by the PRL gene.Prolactin is a peptide hormone discovered by Henry Friesen...
. 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.
Chemistry
Hunkeler, W.; Kyburz, E.; 1982, .The use of an isocyanide
Isocyanide
An isocyanide is an organic compound with the functional group -N≡C. It is the isomer of the related cyanide , hence the prefix iso....
can be seen.