|Systematic (IUPAC) name|
|Formula||C19H26N4O2 · HCl|
|Mol. mass||342.44 g/mol (free base)
378.896 g/mol (HCl)
| (what is this?)
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.
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.
- Turconi M, Nicola M, Quintero MG, Maiocchi L, Micheletti R, Giraldo E, Donetti A. 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. 1990 Aug;33(8):2101-8. PMID 1695682
- Dumuis A, Sebben M, Monferini E, Nicola M, Turconi M, Ladinsky H, Bockaert J. 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. 1991 Mar;343(3):245-51. PMID 1650917
- 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.
- Wang, X; Dergacheva, O; Kamendi, H; Gorini, C; Mendelowitz, D (2007). "5-Hydroxytryptamine 1A/7 and 4alpha receptors differentially prevent opioid-induced inhibition of brain stem cardiorespiratory function.". Hypertension 50 (2): 368–76. doi:10.1161/HYPERTENSIONAHA.107.091033. PMID 17576856.
- 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.
- 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.
- Meyer, LC; Fuller, A; Mitchell, D (2006). "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): R405–13. doi:10.1152/ajpregu.00440.2005. PMID 16166206.
- Bonhaus DW, Loury DN, Jakeman LB, Hsu SA, To ZP, Leung E, Zeitung KD, Eglen RM, Wong EH (October 1994). "[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): 484–93. PMID 7965749.
- Weatherspoon JK, Gonzalez-Alvear GM, Werling LL (May 1997). "Regulation of [3H]norepinephrine release from guinea pig hippocampus by sigma2 receptors". Eur. J. Pharmacol. 326 (2-3): 133–8. doi:10.1016/S0014-2999(97)85407-6. PMID 9196265.
- Liu X, Nuwayhid S, Christie MJ, Kassiou M, Werling LL (June 2001). "Trishomocubanes: novel sigma-receptor ligands modulate amphetamine-stimulated [3H]dopamine release". European Journal of Pharmacology 422 (1–3): 39–45. doi:10.1016/S0014-2999(01)01071-8. PMID 11430911.