Ro15-4513
Encyclopedia
Ro15-4513 is a weak partial inverse agonist
of the benzodiazepine
class of drugs, developed by Hoffmann–La Roche in 1984, and is structurally related to the benzodiazepine antidote
flumazenil
.
. Flumazenil effectively blocks the effects of benzodiazepine agonists such as alprazolam
and diazepam
and so is used for treating overdoses of these drugs but is ineffective in blocking alcohol actions. Ro15-4513 was somewhat less effective than flumazenil at blocking the effects of benzodiazepines, but instead selectively blocked the effects of ethanol
. This meant that in contrast to flumazenil, which is ineffective at treating alcohol overdoses, Ro15-4513 showed potential as a useful alcohol antidote. It is thought that Ro15-4513 antagonizes the effects of ethanol because the azido group at the 8- position of the benzene ring blocks the binding site for ethanol on the α4β3δ subtype of the GABAA receptor; flumazenil, which has a fluorine at this position, does not block this binding site and so does not counteract the effects of ethanol.
Unfortunately Ro15-4513 had several disadvantages that made it unsuitable for development and marketing. Its fairly short half-life means that several repeated doses would have to be given over an extended period, since if only one dose were used it would wear off before the alcohol had been metabolised and the patient would relapse (similar to the problems with renarcotization seen when treating overdoses of long-acting opioids such as methadone
with short-acting antagonists such as naloxone
). Also because of its GABA antagonist effects, Ro15-4513 causes serious side-effects including both anxiety
, and at higher doses, convulsions, which would require careful control of dosing and would cause complications in clinical use. Another problem is that alcohol's effects are not purely mediated by GABA receptors; at higher doses alcohol binds to several other targets as well, so while Ro15-4513 is an effective antidote against moderate levels of alcohol intoxication, it might be ineffective at treating life-threatening overdoses.
Also, Roche was concerned about the legal implications of introducing an alcohol antidote, as Ro15-4513 blocks the effects of ethanol but does not remove it from the bloodstream, which could lead to potential problems, as the effects of the alcohol would be masked only temporarily. As a result, patients might, for instance, feel that they are sober and discharge themselves from hospital once the drug took effect, then become drunk again once it wore off, possibly crashing their car or having other accidents that might lead to legal consequences for Roche.
However, the discovery of Ro15-4513 has been important in elucidating the mechanism of action of ethanol as used as a recreational drug, and this compound could now be used as a template to design a more effective and longer-lasting antidote for ethanol, or alternatively to develop a selective agonist drug that could replicate the beneficial effects of alcohol but with fewer side-effects.
, cerebellum
, and basal ganglia
, as it does not selectively label the GABRA1
subtype.
Inverse agonist
In the field of pharmacology, an inverse agonist is an agent that binds to the same receptor as an agonist but induces a pharmacological response opposite to that agonist....
of the benzodiazepine
Benzodiazepine
A benzodiazepine is a psychoactive drug whose core chemical structure is the fusion of a benzene ring and a diazepine ring...
class of drugs, developed by Hoffmann–La Roche in 1984, and is structurally related to the benzodiazepine 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"....
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...
.
Original development as alcohol antidote
The main interest in Ro15-4513 was as an antidote to alcoholAlcoholic beverage
An alcoholic beverage is a drink containing ethanol, commonly known as alcohol. Alcoholic beverages are divided into three general classes: beers, wines, and spirits. They are legally consumed in most countries, and over 100 countries have laws regulating their production, sale, and consumption...
. Flumazenil effectively blocks the effects of benzodiazepine agonists such as 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...
and 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 so is used for treating overdoses of these drugs but is ineffective in blocking alcohol actions. Ro15-4513 was somewhat less effective than flumazenil at blocking the effects of benzodiazepines, but instead selectively blocked the effects of ethanol
Ethanol
Ethanol, also called ethyl alcohol, pure alcohol, grain alcohol, or drinking alcohol, is a volatile, flammable, colorless liquid. It is a psychoactive drug and one of the oldest recreational drugs. Best known as the type of alcohol found in alcoholic beverages, it is also used in thermometers, as a...
. This meant that in contrast to flumazenil, which is ineffective at treating alcohol overdoses, Ro15-4513 showed potential as a useful alcohol antidote. It is thought that Ro15-4513 antagonizes the effects of ethanol because the azido group at the 8- position of the benzene ring blocks the binding site for ethanol on the α4β3δ subtype of the GABAA receptor; flumazenil, which has a fluorine at this position, does not block this binding site and so does not counteract the effects of ethanol.
Unfortunately Ro15-4513 had several disadvantages that made it unsuitable for development and marketing. Its fairly short half-life means that several repeated doses would have to be given over an extended period, since if only one dose were used it would wear off before the alcohol had been metabolised and the patient would relapse (similar to the problems with renarcotization seen when treating overdoses of long-acting opioids such as methadone
Methadone
Methadone is a synthetic opioid, used medically as an analgesic and a maintenance anti-addictive for use in patients with opioid dependency. It was developed in Germany in 1937...
with short-acting antagonists such as naloxone
Naloxone
Naloxone is an opioid antagonist drug developed by Sankyo in the 1960s. Naloxone is a drug used to counter the effects of opiate overdose, for example heroin or morphine overdose. Naloxone is specifically used to counteract life-threatening depression of the central nervous system and respiratory...
). Also because of its GABA antagonist effects, Ro15-4513 causes serious side-effects including both 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,...
, and at higher doses, convulsions, which would require careful control of dosing and would cause complications in clinical use. Another problem is that alcohol's effects are not purely mediated by GABA receptors; at higher doses alcohol binds to several other targets as well, so while Ro15-4513 is an effective antidote against moderate levels of alcohol intoxication, it might be ineffective at treating life-threatening overdoses.
Also, Roche was concerned about the legal implications of introducing an alcohol antidote, as Ro15-4513 blocks the effects of ethanol but does not remove it from the bloodstream, which could lead to potential problems, as the effects of the alcohol would be masked only temporarily. As a result, patients might, for instance, feel that they are sober and discharge themselves from hospital once the drug took effect, then become drunk again once it wore off, possibly crashing their car or having other accidents that might lead to legal consequences for Roche.
However, the discovery of Ro15-4513 has been important in elucidating the mechanism of action of ethanol as used as a recreational drug, and this compound could now be used as a template to design a more effective and longer-lasting antidote for ethanol, or alternatively to develop a selective agonist drug that could replicate the beneficial effects of alcohol but with fewer side-effects.
Current use in PET Imaging
Labelling Ro15-4513 with carbon-11 leads to the possibility of its use in PET imaging of the brain. The specificity of the compound to a small number of GABA receptor sub-types leads to the generation, with accurate modelling, of detailed images with well-defined limbic and cortical structures. These images can be useful in quantitatively analysing conditions such as addiction, that are known to be, at least in part, associated with the GABAergic system. The images produced are similar to those for labelled flumazenil, though the distribution varies especially in regions such as the occipital lobeOccipital lobe
The occipital lobe is the visual processing center of the mammalian brain containing most of the anatomical region of the visual cortex. The primary visual cortex is Brodmann area 17, commonly called V1...
, cerebellum
Cerebellum
The cerebellum is a region of the brain that plays an important role in motor control. It may also be involved in some cognitive functions such as attention and language, and in regulating fear and pleasure responses, but its movement-related functions are the most solidly established...
, and basal ganglia
Basal ganglia
The basal ganglia are a group of nuclei of varied origin in the brains of vertebrates that act as a cohesive functional unit. They are situated at the base of the forebrain and are strongly connected with the cerebral cortex, thalamus and other brain areas...
, as it does not selectively label the GABRA1
GABRA1
Gamma-aminobutyric acid receptor subunit alpha-1 is a protein that in humans is encoded by the GABRA1 gene.-Further reading:...
subtype.
See also
- Benzodiazepine overdoseBenzodiazepine overdoseBenzodiazepine 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...
- BenzodiazepineBenzodiazepineA benzodiazepine is a psychoactive drug whose core chemical structure is the fusion of a benzene ring and a diazepine ring...
- BretazenilBretazenilBretazenil 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...
- FlumazenilFlumazenilFlumazenil 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...
- ImidazenilImidazenilImidazenil 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....