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 Respiration may refer to: Biology * Cellular respiration, the process in which nutrients are converted into useful energy in a cell ** Anaerobic respiration, cellular respiration without oxygen ** Maintenance respiration, the amount of cellul ...

by activating an area of the brain stem known as the pre-Botzinger complex.

Use

The most obvious practical use of BIMU-8 is to combine it with

opioid Opioids are substances that act on opioid receptors to produce morphine-like effects. Medically they are primarily used for pain relief, including anesthesia. Other medical uses include suppression of diarrhea, replacement therapy for opioid use ...

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 pleasurable or painkilling properties of opiates, which means that if combined with BIMU-8, large therapeutic doses of opiates could theoretically be given to

human Humans (''Homo sapiens'') are the most abundant and widespread species of primate, characterized by bipedalism and exceptional cognitive skills due to a large and complex brain. This has enabled the development of advanced tools, cultu ...

s without risking a decrease in breathing rate. Studies have shown BIMU-8 to be effective in rats at counteracting the respiratory depression caused by the potent opioid

fentanyl Fentanyl, also spelled fentanil, is a very potent synthetic opioid used as a pain medication. Together with other drugs, fentanyl is used for anesthesia. It is also used illicitly as a recreational drug, sometimes mixed with heroin, cocain ...

, 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 5-HT₄ 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. Some other selective 5-HT₄ agonists such as

mosapride Mosapride is a gastroprokinetic agent that acts as a selective 5HT4 agonist. The major active metabolite of mosapride, known as M1, additionally acts as a 5HT3 antagonist, which accelerates gastric emptying throughout the whole of the gastroin ...

and

tegaserod Tegaserod is a 5-HT4 agonist manufactured by Novartis and sold under the names Zelnorm and Zelmac for the management of irritable bowel syndrome and constipation. Approved by the FDA in 2002, it was subsequently removed from the market in 2007 du ...

(the only 5-HT₄ agonists currently licensed for use in humans) have been found not to reduce respiratory depression. On the other hand, another 5-HT₄ 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 5-HT₄ receptor which is activated by BIMU-8 and zacopride, but not by mosapride or tegaserod, or alternatively there may be

functional selectivity Functional selectivity (or “agonist trafficking”, “biased agonism”, “biased signaling”, "ligand bias" and “differential engagement”) is the ligand-dependent selectivity for certain signal transduction pathways relative to a referen ...

involved whereby BIMU-8 and zacopride produce a different physiological response following 5-HT₄ binding compared to other 5-HT₄ agonists. Another alternative to this is that the 5-HT₄ agonist currently available for use in humans do not have great enough potency or bioavailability in the brain to elicit the same effects.

Other activity

Along with several other 5-HT₄ ligands, BIMU-8 was also found to possess significant affinity for the

sigma receptor Sigma receptors (σ-receptors) are protein cell surface receptors that bind ligands such as 4-PPBP (4-phenyl-1-(4-phenylbutyl) piperidine), SA 4503 (cutamesine), ditolylguanidine, dimethyltryptamine, and siramesine. There are two subtypes, ...

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.

References

{{Serotonergics Respiratory agents Antidotes Serotonin receptor agonists Tropanes Benzimidazoles Ureas Lactams Isopropyl compounds

Use

Other activity

See also

References