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BIMU8
Systematic (IUPAC) name
N-[(1R,5S)-8-methyl-8-azabicyclo[3.2.1]oct-3-yl]-2-oxo-3-(propan-2-yl)-2,3-dihydro-1 H-benzimidazole-1-carboxamide hydrochloride
Identifiers
CAS number 134296-40-5
ATC code  ?
PubChem 5311028
ChemSpider 4470566
Chemical data
Formula C 19H26N4O2 · HCl 
Mol. mass 342.44 g/mol (free base)
378.896 g/mol (HCl)
SMILES eMolecules & PubChem
Pharmacokinetic data
Bioavailability  ?
Metabolism  ?
Half life  ?
Excretion  ?
Therapeutic considerations
Pregnancy cat.  ?
Legal status
Routes  ?
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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.[1] 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,[2] 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,[3] 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.[4] On the other hand another 5HT4 agonist zacopride does inhibit respiratory depression in a similar manner to BIMU-8.[5]

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

  1. ^ Manzke T, Guenther U, Ponimaskin E, Haller M, Dutschmann M, Schwarzacher S, Richter D (2003). "5-HT4(a) receptors avert opioid-induced breathing depression without loss of analgesia". Science 301 (5630): 226–9. doi:10.1126/science.1084674. PMID 12855812.  
  2. ^ 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
  3. ^ Meneses A, Hong E (1997). "Effects of 5-HT4 receptor agonists and antagonists in learning". Pharmacol Biochem Behav 56 (3): 347–51. doi:10.1016/S0091-3057(96)00224-9. PMID 9077568.  
  4. ^ 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.
  5. ^ 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
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