BIMU8
# BIMU8

BIMU-8 is a drug which acts as a $5-HT_4$ 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.

## Use

The most obvious practical use of BIMU-8 is to combine it with opioid 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 humans 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, 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 $5-HT_4$ 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 $5-HT_4$ agonists such as mosapride and tegaserod (the only $5-HT_4$ agonists currently licensed for use in humans) have been found not to reduce respiratory depression. On the other hand, another $5-HT_4$ 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 $5-HT_4$ 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 $5-HT_4$ binding compared to other $5-HT_4$ agonists. Another alternative to this is that the $5-HT_4$ 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 $5-HT_4$ ligands, BIMU-8 was also found to possess significant affinity for the sigma receptors, acting as a $σ_2$ antagonist. It is unclear as yet what contribution this additional activity makes to the pharmacological profile of BIMU-8 and other $5-HT_4$ ligands that also show sigma affinity.

