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{{Short description|Chemical compound}} |
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{{Drugbox |
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{{Drugbox |
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| verifiedrevid = 447613417 |
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| Watchedfields = changed |
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| verifiedrevid = 444651941 |
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| IUPAC_name = ''N''-oct-3-yl]-2-oxo-3-(propan-2-yl)-2,3-dihydro-1''H''-benzimidazole-1-carboxamide hydrochloride |
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| IUPAC_name = ''N''-oct-3-yl]-2-oxo-3-(propan-2-yl)-2,3-dihydro-1''H''-benzimidazole-1-carboxamide hydrochloride |
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| image = BIMU8.svg |
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| image = BIMU8.svg |
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<!--Clinical data--> |
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<!--Clinical data--> |
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| tradename = |
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| tradename = |
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| legal_UK = <!-- GSL / P / POM / CD / Class A, B, C --> |
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| legal_UK = <!-- GSL / P / POM / CD / Class A, B, C --> |
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| legal_US = <!-- OTC / Rx-only / Schedule I, II, III, IV, V --> |
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| legal_US = <!-- OTC / Rx-only / Schedule I, II, III, IV, V --> |
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<!--Identifiers--> |
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<!--Identifiers--> |
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| CASNo_Ref = {{cascite|correct|??}} |
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| CAS_number_Ref = {{cascite|correct|??}} |
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| CAS_number = 134296-40-5 |
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| CAS_number = 134296-40-5 |
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| PubChem = 5311028 |
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| PubChem = 5311028 |
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| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}} |
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| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}} |
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| ChemSpiderID = 4470566 |
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| ChemSpiderID = 4470566 |
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<!--Chemical data--> |
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<!--Chemical data--> |
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| C=19 | H=26 | N=4 | O=2 <big>· ]</big> |
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| chemical_formula={{Chem| C|19 | H|26| N|4 | O|2}}· ] |
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| molecular_weight = 342.44 g/mol (free base)<br />378.896 g/mol (HCl) |
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| smiles = Cl.O=C2N(c1ccccc1N2C(=O)NC4C3N(C)(CC3)C4)C(C)C |
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| smiles = Cl.O=C2N(c1ccccc1N2C(=O)NC4C3N(C)(CC3)C4)C(C)C |
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| InChI = 1/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+; |
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| InChIKey = NQYXXIUVFVOJCX-XZPOUAKSBF |
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| StdInChI_Ref = {{stdinchicite|correct|chemspider}} |
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| StdInChI_Ref = {{stdinchicite|correct|chemspider}} |
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| StdInChI = 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+; |
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| StdInChI = 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+; |
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'''BIMU-8''' is a drug which acts as a ] selective ]. BIMU-8 was one of the first compounds of this class. The main action of BIMU-8 is to increase the rate of ] by activating an area of the brain stem known as the ]. |
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'''BIMU-8''' is a drug which acts as a ] selective ]. BIMU-8 was one of the first compounds of this class.<ref>{{cite journal | vauthors = Turconi M, Nicola M, Quintero MG, Maiocchi L, Micheletti R, Giraldo E, Donetti A | title = 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 = Journal of Medicinal Chemistry | volume = 33 | issue = 8 | pages = 2101–2108 | date = August 1990 | pmid = 1695682 | doi = 10.1021/jm00170a009 }}</ref><ref>{{cite journal | vauthors = Dumuis A, Sebben M, Monferini E, Nicola M, Turconi M, Ladinsky H, Bockaert J | title = Azabicycloalkyl benzimidazolone derivatives as a novel class of potent agonists at the 5-HT4 receptor positively coupled to adenylate cyclase in brain | journal = Naunyn-Schmiedeberg's Archives of Pharmacology | volume = 343 | issue = 3 | pages = 245–251 | date = March 1991 | pmid = 1650917 | doi = 10.1007/bf00251122 | s2cid = 3173348 }}</ref> The main action of BIMU-8 is to increase the rate of ] by activating an area of the brain stem known as the ]. |
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== Use == |
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== Use == |
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The most obvious practical use of BIMU-8 is to combine it with ] analgesic drugs in order to counteract the dangerous ] which can occur when opioids are used in excessive doses.<ref>{{cite journal |author=Manzke T, Guenther U, Ponimaskin E, Haller M, Dutschmann M, Schwarzacher S, Richter D |title=5-HT4(a) receptors avert opioid-induced breathing depression without loss of analgesia |journal=Science |volume=301 |issue=5630 |pages=226–9 |year=2003 |pmid=12855812 |doi=10.1126/science.1084674}}</ref> 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 ]s without risking a decrease in breathing rate. Studies have shown BIMU-8 to be effective in ]s at counteracting the respiratory depression caused by the potent opioid ],<ref>{{cite journal | last1 = Wang | first1 = X | last2 = Dergacheva | first2 = O | last3 = Kamendi | first3 = H | last4 = Gorini | first4 = C | last5 = Mendelowitz | first5 = D | title = 5-Hydroxytryptamine 1A/7 and 4alpha receptors differentially prevent opioid-induced inhibition of brain stem cardiorespiratory function. | journal = Hypertension | volume = 50 | issue = 2 | pages = 368–76 | year = 2007 | pmid = 17576856 | doi = 10.1161/HYPERTENSIONAHA.107.091033 }}</ref> which has caused many accidental deaths in humans. However, no human trials of BIMU-8 have yet been carried out. |
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The most obvious practical use of BIMU-8 is to combine it with ] analgesic drugs in order to counteract the dangerous ] which can occur when opioids are used in excessive doses.<ref>{{cite journal | vauthors = Manzke T, Guenther U, Ponimaskin EG, Haller M, Dutschmann M, Schwarzacher S, Richter DW | title = 5-HT4(a) receptors avert opioid-induced breathing depression without loss of analgesia | journal = Science | volume = 301 | issue = 5630 | pages = 226–229 | date = July 2003 | pmid = 12855812 | doi = 10.1126/science.1084674 | bibcode = 2003Sci...301..226M | s2cid = 13641423 }}</ref> 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 ]s without risking a decrease in breathing rate. Studies have shown BIMU-8 to be effective in ]s at counteracting the respiratory depression caused by the potent opioid ],<ref>{{cite journal | vauthors = Wang X, Dergacheva O, Kamendi H, Gorini C, Mendelowitz D | title = 5-Hydroxytryptamine 1A/7 and 4alpha receptors differentially prevent opioid-induced inhibition of brain stem cardiorespiratory function | journal = Hypertension | volume = 50 | issue = 2 | pages = 368–376 | date = August 2007 | pmid = 17576856 | doi = 10.1161/HYPERTENSIONAHA.107.091033 | doi-access = free }}</ref> which has caused many accidental deaths in humans. However, no human trials of BIMU-8 have yet been carried out. |
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Other studies have suggested a role for 5HT<sub>4</sub> agonists in learning and memory,<ref>{{cite journal |author=Meneses A, Hong E |title=Effects of 5-HT4 receptor agonists and antagonists in learning |journal=Pharmacol Biochem Behav |volume=56 |issue=3 |pages=347–51 |year=1997 |pmid=9077568 |doi=10.1016/S0091-3057(96)00224-9}}</ref> and BIMU-8 was found to increase conditioned responses in mice, so this drug might also be useful for improving memory in humans. |
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Other studies have suggested a role for 5-HT<sub>4</sub> agonists in learning and memory,<ref>{{cite journal | vauthors = Meneses A, Hong E | title = Effects of 5-HT4 receptor agonists and antagonists in learning | journal = Pharmacology, Biochemistry, and Behavior | volume = 56 | issue = 3 | pages = 347–351 | date = March 1997 | pmid = 9077568 | doi = 10.1016/S0091-3057(96)00224-9 | s2cid = 11866740 }}</ref> and BIMU-8 was found to increase conditioned responses in mice, so this drug might also be useful for improving memory in humans. |
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Some other selective 5-HT<sub>4</sub> agonists such as ] and ] (the only 5-HT<sub>4</sub> agonists currently licensed for use in humans) have been found not to reduce respiratory depression.<ref name="ReferenceA">{{cite journal | vauthors = Lötsch J, Skarke C, Schneider A, Hummel T, Geisslinger G | title = The 5-hydroxytryptamine 4 receptor agonist mosapride does not antagonize morphine-induced respiratory depression | journal = Clinical Pharmacology and Therapeutics | volume = 78 | issue = 3 | pages = 278–287 | date = September 2005 | pmid = 16153398 | doi = 10.1016/j.clpt.2005.05.010 | s2cid = 45695450 }}</ref> On the other hand, another 5-HT<sub>4</sub> agonist, ], does inhibit respiratory depression in a similar manner to BIMU-8.<ref>{{cite journal | vauthors = Meyer LC, Fuller A, Mitchell D | title = Zacopride and 8-OH-DPAT reverse opioid-induced respiratory depression and hypoxia but not catatonic immobilization in goats | journal = American Journal of Physiology. Regulatory, Integrative and Comparative Physiology | volume = 290 | issue = 2 | pages = R405–R413 | date = February 2006 | pmid = 16166206 | doi = 10.1152/ajpregu.00440.2005 | s2cid = 224414 }}</ref> |
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Interestingly some other selective 5HT<sub>4</sub> agonists such as ] and ] (the only |
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5HT<sub>4</sub> agonists currently licensed for use in humans) have been found not to reduce respiratory depression.<ref>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.</ref> On the other hand another 5HT<sub>4</sub> agonist ] does inhibit respiratory depression in a similar manner to BIMU-8.<ref>{{cite journal | last1 = Meyer | first1 = LC | last2 = Fuller | first2 = A | last3 = Mitchell | first3 = D | title = Zacopride and 8-OH-DPAT reverse opioid-induced respiratory depression and hypoxia but not catatonic immobilization in goats. | journal = American journal of physiology. Regulatory, integrative and comparative physiology | volume = 290 | issue = 2 | pages = R405–13 | year = 2006 | pmid = 16166206 | doi = 10.1152/ajpregu.00440.2005 }}</ref> |
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This suggests that either the anti-respiratory depression action is mediated via a specific subtype of the 5HT<sub>4</sub> receptor which is activated by BIMU-8 and zacopride, but not by mosapride or tegaserod, or alternatively there may be ] involved whereby BIMU-8 and zacopride produce a different physiological response following 5HT<sub>4</sub> binding compared to other 5HT<sub>4</sub> agonists. |
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This suggests that either the anti-respiratory depression action is mediated via a specific subtype of the 5-HT<sub>4</sub> receptor which is activated by BIMU-8 and zacopride, but not by mosapride or tegaserod, or alternatively there may be ] involved whereby BIMU-8 and zacopride produce a different physiological response following 5-HT<sub>4</sub> binding compared to other 5-HT<sub>4</sub> agonists. Another alternative to this is that the 5-HT<sub>4</sub> agonist currently available for use in humans do not have great enough potency or bioavailability in the brain to elicit the same effects.<ref name="ReferenceA"/> |
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==Other activity== |
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==Other activity== |
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Along with several other 5-HT<sub>4</sub> ligands, BIMU-8 was also found to possess significant affinity for the ]s, acting as a ] antagonist.<ref name="pmid7965749">{{cite journal |author=Bonhaus DW, Loury DN, Jakeman LB, Hsu SA, To ZP, Leung E, Zeitung KD, Eglen RM, Wong EH |title=RS-23597-190, a potent 5-hydroxytryptamine4 antagonist labels sigma-1 but not sigma-2 binding sites in guinea pig brain |journal=The Journal of Pharmacology and Experimental Therapeutics |volume=271 |issue=1 |pages=484–93 |year=1994 |month=October |pmid=7965749 |doi= |url=}}</ref><ref>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</ref><ref name="pmid11430911">{{cite journal |author=Liu X, Nuwayhid S, Christie MJ, Kassiou M, Werling LL |title=Trishomocubanes: novel sigma-receptor ligands modulate amphetamine-stimulated dopamine release |journal=European Journal of Pharmacology |volume=422 |issue=1-3 |pages=39–45 |year=2001 |month=June |pmid=11430911 |doi= 10.1016/S0014-2999(01)01071-8|url=}}</ref> It is unclear as yet what contribution this additional activity makes to the pharmacological profile of BIMU-8 and other 5-HT<sub>4</sub> ligands that also show sigma affinity. |
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Along with several other 5-HT<sub>4</sub> ligands, BIMU-8 was also found to possess significant affinity for the ]s, acting as a ] antagonist.<ref name="pmid7965749">{{cite journal | vauthors = Bonhaus DW, Loury DN, Jakeman LB, Hsu SA, To ZP, Leung E, Zeitung KD, Eglen RM, Wong EH | display-authors = 6 | title = RS-23597-190, a potent 5-hydroxytryptamine4 antagonist labels sigma-1 but not sigma-2 binding sites in guinea pig brain | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 271 | issue = 1 | pages = 484–493 | date = October 1994 | pmid = 7965749 }}</ref><ref>{{cite journal | vauthors = Weatherspoon JK, Gonzalez-Alvear GM, Werling LL | title = Regulation of norepinephrine release from guinea pig hippocampus by sigma2 receptors | journal = European Journal of Pharmacology | volume = 326 | issue = 2–3 | pages = 133–138 | date = May 1997 | pmid = 9196265 | doi = 10.1016/S0014-2999(97)85407-6 }}</ref><ref name="pmid11430911">{{cite journal | vauthors = Liu X, Nuwayhid S, Christie MJ, Kassiou M, Werling LL | title = Trishomocubanes: novel sigma-receptor ligands modulate amphetamine-stimulated dopamine release | journal = European Journal of Pharmacology | volume = 422 | issue = 1–3 | pages = 39–45 | date = June 2001 | pmid = 11430911 | doi = 10.1016/S0014-2999(01)01071-8 }}</ref> It is unclear as yet what contribution this additional activity makes to the pharmacological profile of BIMU-8 and other 5-HT<sub>4</sub> ligands that also show sigma affinity. |
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== See also == |
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* ] |
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== References == |
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