BIMU8
Encyclopedia
BIMU-8 is a drug which acts as a 5-HT4 receptor
selective agonist
. BIMU-8 was one of the first compounds of this class. The main action of BIMU-8 is to increase the rate of respiration
by activating an area of the brain stem known as the pre-Botzinger complex
.
analgesic drugs in order to counteract the dangerous respiratory depression which can occur when opioids are used in excessive doses. BIMU-8 does not affect the painkilling properties of opiates, which means that if combined with BIMU-8, large therapeutic doses of opiates could theoretically be given to human
s without risking a decrease in breathing rate. Studies have shown BIMU-8 to be effective in rat
s at counteracting the respiratory depression caused by the potent opioid fentanyl, which has caused many accidental deaths in humans. However, no human trials of BIMU-8 have yet been carried out.
Other studies have suggested a role for 5HT4 agonists in learning and memory, and BIMU-8 was found to increase conditioned responses in mice, so this drug might also be useful for improving memory in humans.
Interestingly some other selective 5HT4 agonists such as mosapride
and tegaserod
(the only
5HT4 agonists currently licensed for use in humans) have been found not to reduce respiratory depression. On the other hand another 5HT4 agonist zacopride
does inhibit respiratory depression in a similar manner to BIMU-8.
This suggests that either the anti-respiratory depression action is mediated via a specific subtype of the 5HT4 receptor which is activated by BIMU-8 and zacopride, but not by mosapride or tegaserod, or alternatively there may be functional selectivity
involved whereby BIMU-8 and zacopride produce a different physiological response following 5HT4 binding compared to other 5HT4 agonists.
s, acting as a σ2
antagonist. It is unclear as yet what contribution this additional activity makes to the pharmacological profile of BIMU-8 and other 5-HT4 ligands that also show sigma affinity.
5-HT4 receptor
5-hydroxytryptamine receptor 4 is a protein that in humans is encoded by the HTR4 gene.- Location :The receptor is located in the alimentary tract, urinary bladder, heart and adrenal gland as well as the central nervous system ....
selective agonist
Agonist
An agonist is a chemical that binds to a receptor of a cell and triggers a response by that cell. Agonists often mimic the action of a naturally occurring substance...
. BIMU-8 was one of the first compounds of this class. The main action of BIMU-8 is to increase the rate of respiration
Respiration (physiology)
'In physiology, respiration is defined as the transport of oxygen from the outside air to the cells within tissues, and the transport of carbon dioxide in the opposite direction...
by activating an area of the brain stem known as the pre-Botzinger complex
Pre-Botzinger complex
The Pre-Bötzinger Complex is a cluster of interneurons in the ventrolateral medulla of the brainstem, which is essential to the generation of respiratory rhythm in mammals...
.
Use
The most obvious practical use of BIMU-8 is to combine it with opioidOpioid
An opioid is a psychoactive chemical that works by binding to opioid receptors, which are found principally in the central and peripheral nervous system and the gastrointestinal tract...
analgesic drugs in order to counteract the dangerous respiratory depression which can occur when opioids are used in excessive doses. BIMU-8 does not affect the painkilling properties of opiates, which means that if combined with BIMU-8, large therapeutic doses of opiates could theoretically be given to human
Human
Humans are the only living species in the Homo genus...
s without risking a decrease in breathing rate. Studies have shown BIMU-8 to be effective in rat
Rat
Rats are various medium-sized, long-tailed rodents of the superfamily Muroidea. "True rats" are members of the genus Rattus, the most important of which to humans are the black rat, Rattus rattus, and the brown rat, Rattus norvegicus...
s at counteracting the respiratory depression caused by the potent opioid fentanyl, which has caused many accidental deaths in humans. However, no human trials of BIMU-8 have yet been carried out.
Other studies have suggested a role for 5HT4 agonists in learning and memory, and BIMU-8 was found to increase conditioned responses in mice, so this drug might also be useful for improving memory in humans.
Interestingly some other selective 5HT4 agonists such as mosapride
Mosapride
Mosapride is a gastroprokinetic agent that acts as a selective 5HT4 agonist which accelerates gastric emptying and is used for the treatment of acid reflux, irritable bowel syndrome and functional dyspepsia....
and tegaserod
Tegaserod
Tegaserod is a 5-HT4 agonist manufactured by Novartis and sold under the name Zelnorm for the management of irritable bowel syndrome and constipation. Approved by the FDA in 2002, it was subsequently removed from the market in 2007 due to FDA concerns about possible adverse cardiovascular effects...
(the only
5HT4 agonists currently licensed for use in humans) have been found not to reduce respiratory depression. On the other hand another 5HT4 agonist zacopride
Zacopride
Zacopride is a potent antagonist at the 5HT3 receptor and an agonist at the 5HT4 receptor. It has anxiolytic and nootropic effects in animal models, with the enantiomer being the more active form...
does inhibit respiratory depression in a similar manner to BIMU-8.
This suggests that either the anti-respiratory depression action is mediated via a specific subtype of the 5HT4 receptor which is activated by BIMU-8 and zacopride, but not by mosapride or tegaserod, or alternatively there may be functional selectivity
Functional Selectivity
Functional selectivity is the ligand-dependent selectivity for certain signal transduction pathways in one and the same receptor. This can be present when a receptor has several possible signal transduction pathways...
involved whereby BIMU-8 and zacopride produce a different physiological response following 5HT4 binding compared to other 5HT4 agonists.
Other activity
Along with several other 5-HT4 ligands, BIMU-8 was also found to possess significant affinity for the sigma receptorSigma receptor
The sigma receptors σ1 and σ2 bind to ligands such as 4-PPBP, SA 4503, ditolylguanidine, dimethyltryptamine and siramesine.- Classification :...
s, acting as a σ2
Sigma-2 receptor
The sigma-2 receptor is a sigma receptor which preferentially binds to siramesine and PB28. Unlike sigma-1 receptor, it has not yet been cloned.Activation of the receptor can cause apoptosis...
antagonist. It is unclear as yet what contribution this additional activity makes to the pharmacological profile of BIMU-8 and other 5-HT4 ligands that also show sigma affinity.