BIMU-8 is a drug which acts as a 5-HT₄ receptor selective

agonist An agonist is a chemical that activates a Receptor (biochemistry), receptor to produce a biological response. Receptors are Cell (biology), cellular proteins whose activation causes the cell to modify what it is currently doing. In contrast, an R ...

. 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 a class of Drug, drugs that derive from, or mimic, natural substances found in the Papaver somniferum, opium poppy plant. Opioids work on opioid receptors in the brain and other organs to produce a variety of morphine-like effects, ...

analgesic drugs in order to counteract the dangerous

respiratory depression Hypoventilation (also known as respiratory depression) occurs when ventilation is inadequate (''hypo'' meaning "below") to perform needed respiratory gas exchange. By definition it causes an increased concentration of carbon dioxide (hypercapni ...

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'') or modern humans are the most common and widespread species of primate, and the last surviving species of the genus ''Homo''. They are Hominidae, great apes characterized by their Prehistory of nakedness and clothing ...

s without risking a decrease in breathing rate. Studies have shown BIMU-8 to be effective in

rat Rats are various medium-sized, long-tailed rodents. Species of rats are found throughout the order Rodentia, but stereotypical rats are found in the genus ''Rattus''. Other rat genera include '' Neotoma'' (pack rats), '' Bandicota'' (bandicoo ...

s at counteracting the respiratory depression caused by the potent opioid

fentanyl Fentanyl is a highly potent synthetic piperidine opioid primarily used as an analgesic (pain medication). It is 30 to 50 times more Potency (pharmacology), potent than heroin and 50 to 100 times more potent than morphine. Its primary Medici ...

, 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 emptying throughout the whole of the gastrointestinal ...

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 d ...

(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 Zacopride is a potent antagonist at the 5-HT3 receptor and an agonist at the 5-HT4 receptor. It has anxiolytic and nootropic effects in animal models, with the (''R'')-(+)-enantiomer being the more active form. It also has antiemetic and pro-re ...

, 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 reference ligand (often the end ...

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 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, sigma-1 rec ...

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