RB-101
Encyclopedia
RB-101 is a drug that acts as an enkephalinase
inhibitor
, which is used in scientific research.
RB-101 is a prodrug
which acts by splitting at the disulfide bond
once inside the brain, to form two selective enzyme inhibitors and blocking both types of the zinc-metallopeptidase enkephalinase enzymes. This inhibits the breakdown of the endogenous opioid peptides known as enkephalin
s. These two enzymes, aminopeptidase N (APN) and neutral endopeptidase
24.11 (NEP), are responsible for the breakdown of both kinds of enkephalin naturally found in the body, and so RB-101 causes a build up of both Met-enkephalin
and Leu-enkephalin
.
These peptides act primarily at the delta opioid receptor
, although they also stimulate the mu opioid receptor
to some extent through a delta-opioid receptor mediated interaction with another peptide cholecystokinin
, and the enzyme-inhibiting effects of RB-101 thus produce indirect stimulation of both of these opioid receptor subtypes. This causes RB-101 to be strongly synergistic with cholecystokinin antagonist
s.
Unlike the more commonly used enkephalinase inhibitor racecadotril, which only acts peripherally and has antidiarrheal effects, RB-101 is able to enter the brain, and thus produces a range of effects, acting as an analgesic
, anxiolytic
and antidepressant
. The antidepressant and anxiolytic actions are thought to be mediated through the delta opioid receptor, while the analgesic effects most likely result from a mix of mu and delta activity. Animal studies suggest that RB-101 is also likely to be useful in relieving the symptoms of acute opioid withdrawal and in the management of opioid dependence.
A significant advantage of inhibiting the breakdown of endogenous opioid peptides rather than stimulating opioid receptors with exogenous drugs is that the levels of opioid peptides are only increased slightly from natural levels, thus avoiding overstimulation and downregulation of the opioid receptors. This means that even when RB-101 is used in high doses for extended periods of time, there is no development of dependence on the drug or tolerance to its analgesic effects. Consequently even though RB-101 is able to produce potent analgesic effects via the opioid system, it is unlikely to be addictive.
Unlike conventional opioid agonists, RB-101 also failed to produce respiratory depression, which suggests it might be a much safer drug than traditional opioid painkillers. RB-101 also powerfully potentiated the effects of traditional analgesics such as ibuprofen
and morphine
, suggesting that it could be used to boost the action of a low dose of normal opioids which would otherwise be ineffective.
RB-101 itself is not orally active and so has not been developed for medical use in humans, however modification of the drug has led to newer orally acting compounds such as RB-120 and RB-3007, which may be more likely to be adopted for medical use if clinical trials are successful.
Enkephalinase
Enkephalinases are enzymes which degrade endogenous enkephalin opioid peptides. They include:* Aminopeptidase N * Neutral endopeptidase * Dipeptidyl peptidase 3 * Carboxypeptidase A6 * Angiotensin-converting enzyme...
inhibitor
Enzyme inhibitor
An enzyme inhibitor is a molecule that binds to enzymes and decreases their activity. Since blocking an enzyme's activity can kill a pathogen or correct a metabolic imbalance, many drugs are enzyme inhibitors. They are also used as herbicides and pesticides...
, which is used in scientific research.
RB-101 is a prodrug
Prodrug
A prodrug is a pharmacological substance administered in an inactive form. Once administered, the prodrug is metabolised in vivo into an active metabolite, a process termed bioactivation. The rationale behind the use of a prodrug is generally for absorption, distribution, metabolism, and...
which acts by splitting at the disulfide bond
Disulfide bond
In chemistry, a disulfide bond is a covalent bond, usually derived by the coupling of two thiol groups. The linkage is also called an SS-bond or disulfide bridge. The overall connectivity is therefore R-S-S-R. The terminology is widely used in biochemistry...
once inside the brain, to form two selective enzyme inhibitors and blocking both types of the zinc-metallopeptidase enkephalinase enzymes. This inhibits the breakdown of the endogenous opioid peptides known as enkephalin
Enkephalin
An enkephalin is a pentapeptide involved in regulating nociception in the body. The enkephalins are termed endogenous ligands, or specifically endorphins, as they are internally derived and bind to the body's opioid receptors. Discovered in 1975, two forms of enkephalin were revealed, one...
s. These two enzymes, aminopeptidase N (APN) and neutral endopeptidase
Neprilysin
Neprilysin, also known as membrane metallo-endopeptidase, neutral endopeptidase , CD10, and common acute lymphoblastic leukemia antigen , is a zinc-dependent metalloprotease enzyme that degrades a number of small secreted peptides, most notably the amyloid beta peptide whose abnormal misfolding and...
24.11 (NEP), are responsible for the breakdown of both kinds of enkephalin naturally found in the body, and so RB-101 causes a build up of both Met-enkephalin
Met-enkephalin
[Met]enkephalin, sometimes referred to as opioid growth factor , is a naturally-occurring, endogenous opioid peptide that has opioid effects of a relatively short duration. It is one of the two forms of enkephalin, the other being [leu]enkephalin...
and Leu-enkephalin
Leu-enkephalin
Leu-enkephalin is an endogenous opioid peptide neurotransmitter with the amino acid sequence Tyr-Gly-Gly-Phe-Leu that is found naturally in the brains of many animals, including humans. It is one of the two forms of enkephalin; the other is met-enkephalin. The tyrosine residue at position 1 is...
.
These peptides act primarily at the delta opioid receptor
Delta Opioid receptor
The δ-opioid receptors, also known as delta opioid receptor or simply delta receptor, abbreviated DOR, is an opioid receptor that has enkephalins as its endogenous ligands.-Function:...
, although they also stimulate the mu opioid receptor
Mu Opioid receptor
The μ-opioid receptors are a class of opioid receptors with high affinity for enkephalins and beta-endorphin but low affinity for dynorphins. They are also referred to as μ opioid peptide receptors. The prototypical μ receptor agonist is the opium alkaloid morphine; μ refers to morphine...
to some extent through a delta-opioid receptor mediated interaction with another peptide cholecystokinin
Cholecystokinin
Cholecystokinin is a peptide hormone of the gastrointestinal system responsible for stimulating the digestion of fat and protein...
, and the enzyme-inhibiting effects of RB-101 thus produce indirect stimulation of both of these opioid receptor subtypes. This causes RB-101 to be strongly synergistic with cholecystokinin antagonist
Cholecystokinin antagonist
A Cholecystokinin antagonist is a specific type of receptor antagonist which blocks the receptor sites for the peptide hormone Cholecystokinin ....
s.
Unlike the more commonly used enkephalinase inhibitor racecadotril, which only acts peripherally and has antidiarrheal effects, RB-101 is able to enter the brain, and thus produces a range of effects, acting as an analgesic
Analgesic
An analgesic is any member of the group of drugs used to relieve pain . The word analgesic derives from Greek an- and algos ....
, anxiolytic
Anxiolytic
An anxiolytic is a drug used for the treatment of anxiety, and its related psychological and physical symptoms...
and antidepressant
Antidepressant
An antidepressant is a psychiatric medication used to alleviate mood disorders, such as major depression and dysthymia and anxiety disorders such as social anxiety disorder. According to Gelder, Mayou &*Geddes people with a depressive illness will experience a therapeutic effect to their mood;...
. The antidepressant and anxiolytic actions are thought to be mediated through the delta opioid receptor, while the analgesic effects most likely result from a mix of mu and delta activity. Animal studies suggest that RB-101 is also likely to be useful in relieving the symptoms of acute opioid withdrawal and in the management of opioid dependence.
A significant advantage of inhibiting the breakdown of endogenous opioid peptides rather than stimulating opioid receptors with exogenous drugs is that the levels of opioid peptides are only increased slightly from natural levels, thus avoiding overstimulation and downregulation of the opioid receptors. This means that even when RB-101 is used in high doses for extended periods of time, there is no development of dependence on the drug or tolerance to its analgesic effects. Consequently even though RB-101 is able to produce potent analgesic effects via the opioid system, it is unlikely to be addictive.
Unlike conventional opioid agonists, RB-101 also failed to produce respiratory depression, which suggests it might be a much safer drug than traditional opioid painkillers. RB-101 also powerfully potentiated the effects of traditional analgesics such as ibuprofen
Ibuprofen
Ibuprofen is a nonsteroidal anti-inflammatory drug used for relief of symptoms of arthritis, fever, as an analgesic , especially where there is an inflammatory component, and dysmenorrhea....
and morphine
Morphine
Morphine is a potent opiate analgesic medication and is considered to be the prototypical opioid. It was first isolated in 1804 by Friedrich Sertürner, first distributed by same in 1817, and first commercially sold by Merck in 1827, which at the time was a single small chemists' shop. It was more...
, suggesting that it could be used to boost the action of a low dose of normal opioids which would otherwise be ineffective.
RB-101 itself is not orally active and so has not been developed for medical use in humans, however modification of the drug has led to newer orally acting compounds such as RB-120 and RB-3007, which may be more likely to be adopted for medical use if clinical trials are successful.