BIMU8

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.

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 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 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.

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