BIMU-8 is a drug which acts as a5-HT4 receptor selectiveagonist. BIMU-8 was one of the first compounds of this class.[1][2] The main action of BIMU-8 is to increase the rate ofrespiration by activating an area of the brain stem known as thepre-Botzinger complex.
The most obvious practical use of BIMU-8 is to combine it withopioid analgesic drugs in order to counteract the dangerousrespiratory 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 tohumans without risking a decrease in breathing rate. Studies have shown BIMU-8 to be effective inrats at counteracting the respiratory depression caused by the potent opioidfentanyl,[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 asmosapride andtegaserod (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 befunctional 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]
Along with several other 5-HT4 ligands, BIMU-8 was also found to possess significant affinity for thesigma receptors, acting as aσ2 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.
^Turconi M, Nicola M, Quintero MG, Maiocchi L, Micheletti R, Giraldo E, Donetti A (August 1990). "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.doi:10.1021/jm00170a009.PMID1695682.
^Dumuis A, Sebben M, Monferini E, Nicola M, Turconi M, Ladinsky H, Bockaert J (March 1991). "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.doi:10.1007/bf00251122.PMID1650917.S2CID3173348.
^abLötsch J, Skarke C, Schneider A, Hummel T, Geisslinger G (September 2005). "The 5-hydroxytryptamine 4 receptor agonist mosapride does not antagonize morphine-induced respiratory depression".Clinical Pharmacology and Therapeutics.78 (3):278–287.doi:10.1016/j.clpt.2005.05.010.PMID16153398.S2CID45695450.
^Meyer LC, Fuller A, Mitchell D (February 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 –R413.doi:10.1152/ajpregu.00440.2005.PMID16166206.S2CID224414.
^Bonhaus DW, Loury DN, Jakeman LB, Hsu SA, To ZP, Leung E, et al. (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):484–493.PMID7965749.
^Weatherspoon JK, Gonzalez-Alvear GM, Werling LL (May 1997). "Regulation of [3H]norepinephrine release from guinea pig hippocampus by sigma2 receptors".European Journal of Pharmacology.326 (2–3):133–138.doi:10.1016/S0014-2999(97)85407-6.PMID9196265.
