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Chemical Compound Review

oxotremorine-M     trimethyl-[4-(2- oxopyrrolidin-1-yl)but-2...

Synonyms: Lopac-O-100, Tocris-1067, SureCN4542695, KBioSS_002548, CHEBI:38322, ...
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Disease relevance of Oxotremorine M

  • Muscarinic receptor-mediated NF-kappaB activation was confirmed by observing the translocation of the active subunit (p65) of NF-kappaB to the nucleus by the muscarinic agonist, oxotremorine M (oxoM), in SH-SY5Y neuroblastoma cells expressing muscarinic receptors that are predominantly of the M3 subtype [1].
  • Exposure to either pertussis toxin or the anti-Go alpha antiserum 9072 but not to cholera toxin or the anti-Gs alpha antiserum 1191 reduced the high-affinity binding of oxotremorine M to muscarinic receptors [2].
  • Exposure of cells permeabilized with digitonin, streptolysin-O, or the alpha-toxin from Staphylococcus aureus to oxotremorine-M (Oxo-M) for 30 min resulted in a 25-30% reduction in the number of cell surface mAChRs, as monitored by the loss of N[3H]methylscopolamine ([3H]NMS) binding sites [3].
  • 2. Acetylcholine (ACh) or nicotine, and muscarine or oxotremorine-M (OX-M) induced membrane depolarization with rapid and slow time courses respectively, followed by repetitive generation of action potentials in the ganglion cell [4].
  • By comparing the response magnitude and the effectiveness in evoking a response, the rank order for evoking excitation, the primary response, was found to be: OM > CCh > ACh approximately McN, which is consistent with that (OM > CCh > McN) for facilitating lordosis reported by others [5].

Psychiatry related information on Oxotremorine M


High impact information on Oxotremorine M

  • Modulation of N- and L-type Ca2+ channels by oxotremorine-M (oxo-M) acting on muscarinic receptors and norepinephrine (NE) acting on alpha-adrenergic receptors was studied in superior cervical ganglion neurons [9].
  • To study the potential role of the M(3) muscarinic receptor subtype in cholinergic stimulation of insulin release, we initially examined the effect of the muscarinic agonist, oxotremorine-M (Oxo-M), on insulin secretion from isolated pancreatic islets prepared from wild-type (WT) and M(3) receptor-deficient mice (M3(+/-) and M3(-/-) mice) [10].
  • Pretreatment with oxotremorine-M, a selective agonist of muscarinic receptors that are expressed endogenously in these cells, did not affect the accumulation of p53 but greatly attenuated caspase-3 activation and protected from cell death to nearly the same extent as treatment with a general caspase inhibitor [11].
  • Likely the most proximal of these events to muscarinic receptor activation, mitochondrial Bax accumulation, also was attenuated by oxotremorine-M treatment after treatment with H(2)O(2) or rotenone [11].
  • In contrast, when oxotremorine-M-stimulated phosphoinositide hydrolysis was inhibited by depletion of extracellular Ca2+, no reduction in the extent of receptor sequestration was observed [12].

Chemical compound and disease context of Oxotremorine M


Biological context of Oxotremorine M


Anatomical context of Oxotremorine M


Associations of Oxotremorine M with other chemical compounds

  • Potentiation of oxotremorine-M-stimulated inositol lipid hydrolysis observed in the presence of either norepinephrine or isoproterenol was reduced in the absence of added Ca2+ [26].
  • The highest degrees of positive cooperativity were observed between (-)-eburnamonine and pilocarpine and (-)-eburnamonine and oxotremorine-M on the M2 receptors (25- and 7-fold increases in affinity, respectively) and between brucine and pentylthio-TZTP on the M2 and brucine and carbachol on the M1 receptors (8-fold increases in affinity) [27].
  • When assayed under conditions similar to those employed for the fluorescence measurements, EGTA also inhibited both the basal and oxotremorine-M-stimulated release of inositol phosphates by 45-61% [28].
  • Despite the low affinity of bethanechol for the M2 receptor, it was an efficacious agonist (maximal response equivalent to that of oxotremorine-M; relative efficacy = 0.6) at this subtype, whereas it was a partial agonist (60%) with lesser efficacy in the clonal M4 system [29].
  • In the absence of retigabine, oxotremorine M depolarised the neurons and elicited action potential discharges in 8 of 23 neurons; in its presence, oxotremorine M still caused equal depolarisations, but always failed to trigger action potentials [30].

Gene context of Oxotremorine M

  • Occupation of just 15% of the M1 receptors in mouse hippocampus was required for maximal efficacy of oxotremorine-M-stimulated GTP-gamma-35S binding indicating a substantial level of spare receptors [31].
  • Pretreatment of the cells with muscarinic receptor agonist, oxotremorine M (Oxo-M), enhanced IL-2 production induced by phorbol 12-myristate 13-acetate (PMA)/A23187, while Oxo-M by itself did not affect IL-2 production [32].
  • Heteromeric KCNQ2/KCNQ3 currents were modulated by the muscarinic agonist oxotremorine-M (oxo-M) in a manner having all of the characteristics of modulation of native M current in sympathetic neurons [33].
  • However, in the presence of the M2 and M4 subtype-preferring antagonist himbacine, oxotremorine-M caused a large increase in the sIPSC frequency [34].
  • In M2 or M4 single-KO mice, oxotremorine-M produced a variable effect on sIPSCs; it increased the frequency of sIPSCs in some cells but decreased the sIPSC frequency in other neurons [34].

Analytical, diagnostic and therapeutic context of Oxotremorine M


  1. Nuclear Factor-{kappa}B Activated by Capacitative Ca2+ Entry Enhances Muscarinic Receptor-mediated Soluble Amyloid Precursor Protein (sAPP{alpha}) Release in SH-SY5Y Cells. Choi, S., Kim, J.H., Roh, E.J., Ko, M.J., Jung, J.E., Kim, H.J. J. Biol. Chem. (2006) [Pubmed]
  2. Characterization of the G protein involved in the muscarinic stimulation of adenylyl cyclase of rat olfactory bulb. Olianas, M.C., Onali, P. Mol. Pharmacol. (1996) [Pubmed]
  3. Sequestration of muscarinic cholinergic receptors in permeabilized neuroblastoma cells. Slowiejko, D.M., Levey, A.I., Fisher, S.K. J. Neurochem. (1994) [Pubmed]
  4. An electrophysiological study of muscarinic and nicotinic receptors of rat paratracheal ganglion neurons and their inhibition by Z-338. Kanemoto, Y., Ishibashi, H., Doi, A., Akaike, N., Ito, Y. Br. J. Pharmacol. (2002) [Pubmed]
  5. In vitro electro-pharmacological and autoradiographic analyses of muscarinic receptor subtypes in rat hypothalamic ventromedial nucleus: implications for cholinergic regulation of lordosis. Kow, L.M., Tsai, Y.F., Weiland, N.G., McEwen, B.S., Pfaff, D.W. Brain Res. (1995) [Pubmed]
  6. Effect of specific M1, M2 muscarinic receptor agonists on REM sleep generation. Velazquez-Moctezuma, J., Gillin, J.C., Shiromani, P.J. Brain Res. (1989) [Pubmed]
  7. Role of cholinergic receptors in locomotion induced by scopolamine and oxotremorine-M. Chintoh, A., Fulton, J., Koziel, N., Aziz, M., Sud, M., Yeomans, J.S. Pharmacol. Biochem. Behav. (2003) [Pubmed]
  8. Acetylcholine muscarinic M2 receptor stimulated [35S]GTP gamma S binding shows regional selective changes in Alzheimer's disease postmortem brain. Cowburn, R.F., Wiehager, B., Ravid, R., Winblad, B. Neurodegeneration : a journal for neurodegenerative disorders, neuroprotection, and neuroregeneration. (1996) [Pubmed]
  9. Inhibition of N- and L-type calcium channels by muscarinic receptor activation in rat sympathetic neurons. Mathie, A., Bernheim, L., Hille, B. Neuron (1992) [Pubmed]
  10. Muscarinic stimulation of pancreatic insulin and glucagon release is abolished in m3 muscarinic acetylcholine receptor-deficient mice. Duttaroy, A., Zimliki, C.L., Gautam, D., Cui, Y., Mears, D., Wess, J. Diabetes (2004) [Pubmed]
  11. Muscarinic receptor activation protects cells from apoptotic effects of DNA damage, oxidative stress, and mitochondrial inhibition. De Sarno, P., Shestopal, S.A., King, T.D., Zmijewska, A., Song, L., Jope, R.S. J. Biol. Chem. (2003) [Pubmed]
  12. The aminosteroid U-73122 inhibits muscarinic receptor sequestration and phosphoinositide hydrolysis in SK-N-SH neuroblastoma cells. A role for Gp in receptor compartmentation. Thompson, A.K., Mostafapour, S.P., Denlinger, L.C., Bleasdale, J.E., Fisher, S.K. J. Biol. Chem. (1991) [Pubmed]
  13. Agonist-induced endocytosis of muscarinic cholinergic receptors: relationship to stimulated phosphoinositide turnover. Sorensen, S.D., McEwen, E.L., Linseman, D.A., Fisher, S.K. J. Neurochem. (1997) [Pubmed]
  14. Pertussis toxin blocks M2 muscarinic receptor-mediated effects on contraction and cyclic AMP in the guinea pig ileum, but not M3-mediated contractions and phosphoinositide hydrolysis. Thomas, E.A., Ehlert, F.J. J. Pharmacol. Exp. Ther. (1994) [Pubmed]
  15. Acetylcholine-induced desensitization of muscarinic contractile response in Guinea pig ileum is inhibited by pertussis toxin treatment. Ehlert, F.J., Ansari, K.Z., Shehnaz, D., Sawyer, G.W., Griffin, M.T. J. Pharmacol. Exp. Ther. (2001) [Pubmed]
  16. Binding and functional selectivity of himbacine for cloned and neuronal muscarinic receptors. Miller, J.H., Aagaard, P.J., Gibson, V.A., McKinney, M. J. Pharmacol. Exp. Ther. (1992) [Pubmed]
  17. Comparison of functional antagonism between isoproterenol and M2 muscarinic receptors in guinea pig ileum and trachea. Ostrom, R.S., Ehlert, F.J. J. Pharmacol. Exp. Ther. (1999) [Pubmed]
  18. The binding of a 2-chloroethylamine derivative of oxotremorine (BM 123) to muscarinic receptors in the rat cerebral cortex. Ehlert, F.J., Jenden, D.J. Mol. Pharmacol. (1985) [Pubmed]
  19. An agonist that is selective for adenylate cyclase-coupled muscarinic receptors. Baumgold, J., Drobnick, A. Mol. Pharmacol. (1989) [Pubmed]
  20. Activation of nicotinic acetylcholine receptors patterns network activity in the rodent hippocampus. Cobb, S.R., Bulters, D.O., Suchak, S., Riedel, G., Morris, R.G., Davies, C.H. J. Physiol. (Lond.) (1999) [Pubmed]
  21. Blockade of GABA(B) receptors facilitates muscarinic agonist-induced epileptiform activity in immature rat piriform cortex in vitro. Libri, V., Constanti, A., Postlethwaite, M., Bowery, N.G. Naunyn Schmiedebergs Arch. Pharmacol. (1998) [Pubmed]
  22. Effect of chronic cholinergic denervation on the m1 muscarinic receptor mechanism. Pearce, B.D., Liskowsky, D.R., Potter, L.T. Neurobiol. Aging (1992) [Pubmed]
  23. Regional differences in the coupling of muscarinic receptors to inositol phospholipid hydrolysis in guinea pig brain. Fisher, S.K., Bartus, R.T. J. Neurochem. (1985) [Pubmed]
  24. Modulation of phosphatidylserine synthesis by a muscarinic receptor occupancy in human neuroblastoma cell line LA-N-1. Mikhaevitch, I.S., Singh, I.N., Sorrentino, G., Massarelli, R., Kanfer, J.N. Biochem. J. (1994) [Pubmed]
  25. Protein kinase C shifts the voltage dependence of KCNQ/M channels expressed in Xenopus oocytes. Nakajo, K., Kubo, Y. J. Physiol. (Lond.) (2005) [Pubmed]
  26. Cyclic AMP potentiates receptor-stimulated phosphoinositide hydrolysis in human neuroepithelioma cells. Fisher, S.K., McEwen, E.L., Lovell, S.C., Landon, R.E. Mol. Pharmacol. (1992) [Pubmed]
  27. Positive cooperativity of acetylcholine and other agonists with allosteric ligands on muscarinic acetylcholine receptors. Jakubík, J., Bacáková, L., El-Fakahany, E.E., Tucek, S. Mol. Pharmacol. (1997) [Pubmed]
  28. Muscarinic receptor regulation of cytoplasmic Ca2+ concentrations in human SK-N-SH neuroblastoma cells: Ca2+ requirements for phospholipase C activation. Fisher, S.K., Domask, L.M., Roland, R.M. Mol. Pharmacol. (1989) [Pubmed]
  29. Interactions of agonists with M2 and M4 muscarinic receptor subtypes mediating cyclic AMP inhibition. McKinney, M., Miller, J.H., Gibson, V.A., Nickelson, L., Aksoy, S. Mol. Pharmacol. (1991) [Pubmed]
  30. Activation of M1 muscarinic receptors triggers transmitter release from rat sympathetic neurons through an inhibition of M-type K+ channels. Lechner, S.G., Mayer, M., Boehm, S. J. Physiol. (Lond.) (2003) [Pubmed]
  31. M1 muscarinic receptor signaling in mouse hippocampus and cortex. Porter, A.C., Bymaster, F.P., DeLapp, N.W., Yamada, M., Wess, J., Hamilton, S.E., Nathanson, N.M., Felder, C.C. Brain Res. (2002) [Pubmed]
  32. Extracellular signal regulated protein kinase and c-jun N-terminal kinase are involved in ml muscarinic receptor-enhanced interleukin-2 production pathway in Jurkat cells. Fujino, H., Uehara, T., Murayama, T., Okuma, Y., Ariga, H., Nomura, Y. Biol. Pharm. Bull. (2000) [Pubmed]
  33. Reconstitution of muscarinic modulation of the KCNQ2/KCNQ3 K(+) channels that underlie the neuronal M current. Shapiro, M.S., Roche, J.P., Kaftan, E.J., Cruzblanca, H., Mackie, K., Hille, B. J. Neurosci. (2000) [Pubmed]
  34. Opposing functions of spinal M2, M3, and M4 receptor subtypes in regulation of GABAergic inputs to dorsal horn neurons revealed by muscarinic receptor knockout mice. Zhang, H.M., Chen, S.R., Matsui, M., Gautam, D., Wess, J., Pan, H.L. Mol. Pharmacol. (2006) [Pubmed]
  35. Effects of an alkylating derivative of oxotremorine (BM 123A) on heart rate, muscarinic receptors and adenylate cyclase activity in the rabbit myocardium. Ehlert, F.J. J. Pharmacol. Exp. Ther. (1987) [Pubmed]
  36. Persistent muscarinic excitation in guinea-pig olfactory cortex neurons: involvement of a slow post-stimulus afterdepolarizing current. Constanti, A., Bagetta, G., Libri, V. Neuroscience (1993) [Pubmed]
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