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BIMU8

Identifiers
IUPAC name N-oct-3-yl]-2-oxo-3-(propan-2-yl)-2,3-dihydro-1H-benzimidazole-1-carboxamide hydrochloride
CAS Number	134296-40-5
PubChem CID	5311028
ChemSpider	4470566
Chemical and physical data
Formula	C19H26N4O2 · HCl
Molar mass	Expression error: Unexpected < operator342.44 g/mol (free base) 378.896 g/mol (HCl)Expression error: Unexpected < operator
3D model (JSmol)	Interactive image
SMILES Cl.O=C2N(c1ccccc1N2C(=O)NC4C3N(C)(CC3)C4)C(C)C
InChI InChI=1S/C19H26N4O2.ClH/c1-12(2)22-16-6-4-5-7-17(16)23(19(22)25)18(24)20-13-10-14-8-9-15(11-13)21(14)3;/h4-7,12-15H,8-11H2,1-3H3,(H,20,24);1H/t13?,14-,15+; Key:NQYXXIUVFVOJCX-XZPOUAKSSA-N
(verify)

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. 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.

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.{{cite journal}}: CS1 maint: multiple names: authors list (link)
2. 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.
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 (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.
6. Bonhaus DW, Loury DN, Jakeman LB, Hsu SA, To ZP, Leung E, Zeitung KD, Eglen RM, Wong EH (1994). "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. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
7. Weatherspoon JK, Gonzalez-Alvear GM, Werling LL. Regulation of norepinephrine release from guinea pig hippocampus by sigma2 receptors. European Journal of Pharmacology. 1997 May 20;326(2-3):133-8. PMID 9196265
8. Liu X, Nuwayhid S, Christie MJ, Kassiou M, Werling LL (2001). "Trishomocubanes: novel sigma-receptor ligands modulate amphetamine-stimulated dopamine release". European Journal of Pharmacology. 422 (1–3): 39–45. doi:10.1016/S0014-2999(01)01071-8. PMID 11430911. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)

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