Chemistry:BIMU8

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Short description: Chemical compound
BIMU8
BIMU8.svg
Identifiers
CAS Number
PubChem CID
ChemSpider
Chemical and physical data
FormulaC19H26N4O2· HCl
3D model (JSmol)
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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.[1][2] 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.[3] 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,[4] 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,[5] 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 and tegaserod (the only 5-HT4 agonists currently licensed for use in humans) have been found not to reduce respiratory depression.[6] On the other hand, another 5-HT4 agonist, zacopride, does inhibit respiratory depression in a similar manner to BIMU-8.[7]

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 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.[6]

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.[8][9][10] 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.

See also

References

  1. ↑ "Synthesis of a new class of 2,3-dihydro-2-oxo-1H-benzimidazole-1-carboxylic acid derivatives as highly potent 5-HT3 receptor antagonists". Journal of Medicinal Chemistry 33 (8): 2101–2108. August 1990. doi:10.1021/jm00170a009. PMID 1695682. 
  2. ↑ "Azabicycloalkyl benzimidazolone derivatives as a novel class of potent agonists at the 5-HT4 receptor positively coupled to adenylate cyclase in brain". Naunyn-Schmiedeberg's Archives of Pharmacology 343 (3): 245–251. March 1991. doi:10.1007/bf00251122. PMID 1650917. 
  3. ↑ "5-HT4(a) receptors avert opioid-induced breathing depression without loss of analgesia". Science 301 (5630): 226–229. July 2003. doi:10.1126/science.1084674. PMID 12855812. Bibcode: 2003Sci...301..226M. 
  4. ↑ "5-Hydroxytryptamine 1A/7 and 4alpha receptors differentially prevent opioid-induced inhibition of brain stem cardiorespiratory function". Hypertension 50 (2): 368–376. August 2007. doi:10.1161/HYPERTENSIONAHA.107.091033. PMID 17576856. 
  5. ↑ "Effects of 5-HT4 receptor agonists and antagonists in learning". Pharmacology, Biochemistry, and Behavior 56 (3): 347–351. March 1997. doi:10.1016/S0091-3057(96)00224-9. PMID 9077568. 
  6. ↑ 6.0 6.1 "The 5-hydroxytryptamine 4 receptor agonist mosapride does not antagonize morphine-induced respiratory depression". Clinical Pharmacology and Therapeutics 78 (3): 278–287. September 2005. doi:10.1016/j.clpt.2005.05.010. PMID 16153398. 
  7. ↑ "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 290 (2): R405–R413. February 2006. doi:10.1152/ajpregu.00440.2005. PMID 16166206. 
  8. ↑ "[3H]RS-23597-190, a potent 5-hydroxytryptamine4 antagonist labels sigma-1 but not sigma-2 binding sites in guinea pig brain". The Journal of Pharmacology and Experimental Therapeutics 271 (1): 484–493. October 1994. PMID 7965749. 
  9. ↑ "Regulation of [3H]norepinephrine release from guinea pig hippocampus by sigma2 receptors". European Journal of Pharmacology 326 (2–3): 133–138. May 1997. doi:10.1016/S0014-2999(97)85407-6. PMID 9196265. 
  10. ↑ "Trishomocubanes: novel sigma-receptor ligands modulate amphetamine-stimulated [3H]dopamine release". European Journal of Pharmacology 422 (1–3): 39–45. June 2001. doi:10.1016/S0014-2999(01)01071-8. PMID 11430911. 



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