|Chemical and physical data|
|Molar mass||342.44 g/mol (free base)
378.896 g/mol (HCl)
|3D model (Jmol)||Interactive image|
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 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, 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, 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 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. On the other hand, another 5-HT4 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 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.
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 euphoria or 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 (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.