BIMU8

Drugbox
IUPAC_name = endo-N-8- methyl-8-azabicyclo [3.2.1] oct-3-yl)-2,3-dihydro-3-isopropyl-2-oxo-1H-benzimidazol-1-carboxamide

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CAS_number = 134296-40-5
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PubChem = 5311028
DrugBank =
C=19|H=26|N=4|O=2
molecular_weight = 342.44 g/mol
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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. [cite journal |author=Manzke T, Guenther U, Ponimaskin E, Haller M, Dutschmann M, Schwarzacher S, Richter D |title=5-HT4(a) receptors avert opioid-induced breathing depression without loss of analgesia |journal=Science |volume=301 |issue=5630 |pages=226–9 |year=2003 |pmid=12855812 |doi=10.1126/science.1084674] 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, [Wang X, Dergacheva O, Kamendi H, Gorini C, Mendelowitz D. 5-Hydroxytryptamine 1A/7 and 4alpha receptors differentially prevent opioid-induced inhibition of brain stem cardiorespiratory function. "Hypertension". 2007 Aug;50(2):368-76. PMID 17576856] 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, [cite journal |author=Meneses A, Hong E |title=Effects of 5-HT4 receptor agonists and antagonists in learning |journal=Pharmacol Biochem Behav |volume=56 |issue=3 |pages=347–51 |year=1997 |pmid=9077568 |doi=10.1016/S0091-3057(96)00224-9] 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 only5HT₄ agonists currently licensed for use in humans) have been found not to reduce respiratory depression. [Lotsch J, Skarke C, Schneider A, Hummel T, Geisslinger G. The 5-hydroxytryptamine 4 receptor agonist mosapride does not antagonize morphine-induced respiratory depression. "Clinical Pharmacology and Therapeutics". 2005 Sep;78(3):278-87.] On the other hand another 5HT₄ agonist zacopride does inhibit respiratory depression in a similar manner to BIMU-8. [Meyer LC, Fuller A, Mitchell D. Zacopride and 8-OH-DPAT reverse opioid-induced respiratory depression and hypoxia but not catatonic immobilization in goats. "American Journal of Physiology. Regulatory, Integrative and Comparative Physiology". 2006 Feb;290(2):R405-13. PMID 16166206]

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.

References

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