Inhibition of intestinal motility by the putative BKCa channel opener LDD175
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LDD175 (4-chloro-7-trifluoromethyl-10H-benzo[4,5]furo[3,2-b]indole-1-carboxylic acid) is a benzofuroindole compound characterized previously as a potent opener of the large conductance calcium activated (BKCa) channels. Activators of the BKCa channels are potential therapies for smooth muscle hyperactivity disorders. The present study investigates the influence of LDD175 on the mechanical activity of the ileum smooth muscle. LDD175 inhibited spontaneous contractions of the ileum in a concentration-dependent manner (pEC50=5.9 ± 0.1) (Emax=96 ± 1.0% at 100 μM, n=3). It also remarkably inhibited contractions due to acetylcholine (ACh) (pEC50=5.3 ± 0.1)(Emax=97.7 ± 2.3%, n=6) and electrical field stimulation (EFS) (pEC50=5.5 ± 0.1) (Emax=83.3 ± 6.0%, n=6). In strips precontracted by 20 mM KCl, LDD175 significantly reduced the contractions yielding a pEC50 of 6.1 ± 0.1 and Emax of 96.6 ± 0.9%, (n=6). In 60 mM KCl, a concentration-dependent inhibition was observed with respective pEC50 and Emax values of 4.1 ± 0.1 and 50.8 ± 5.0% (n=3). BKCa channel blockers iberiotoxin (IbTX) and tetraethylammonium chloride (TEA, 1 mM) attenuated the relaxative effect of LDD175 but not barium chloride (BaCl2), and glibenclamide (KIR and KATP channel blockers, respectively). These data demonstrate the antispasmodic activity of LDD175 attributable to the potentiation of the BKCa channels.
Key wordsLDD175 Benzofuroindole BKCa Channels Ileum Antispasmodic IbTX
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- Butera, J. A., Antane, S. A., Hirth, B., Lennox, J. R., Sheldon, J. H., Norton, N. W., Warga, D., and Argentieri, T. M., Synthesis and potassium channel opening activity of substituted 10H-benzo[4,5]furo[3,2-b]indole- and 5,10-dihydro-indeno[1,2-b]indole-1-carboxylic acids. Bioorg. Med. Chem. Lett., 11, 2093–2097 (2001).PubMedCrossRefGoogle Scholar
- Calderone, V., Large-conductance, Ca(2+)-activated K(+) channels: function, pharmacology and drugs: Curr. Med. Chem. Bentham Science Publishers, IL, USA. pp. 1385–1395 (2002).Google Scholar
- Cook, N. S. and Quast, U., Potassium channel pharmacology. In Cook, N.S. (Eds) Potassium channels, structure, classification, function and therapeutic potential. Ellis Horwood, Chichester, pp. 181–255 (1990).Google Scholar
- Galvez, A., Gimenez-Gallego, G., Reuben, J. P., Roy-Contancin, L., Feigenbaum, P., Kaczorowski, G., and Garcia, M. L., Purification and characterization of a unique, potent, peptidyl probe for the high conductance calcium-activated potassium channel from venom of the scorpion buthus tamulus. J. Biol. Chem., 265, 11083–11090 (1990).PubMedGoogle Scholar
- Garcia, M. L. and Kaczorowski, G. J., Pharmacology of high-conductance Ca2+-activated potassium channels. In: Potassium Channels Cardiovascular Biology, (Ed.) Archer, S. L. and Rusch, N.J., New York: Kluwer Academic/Plenum Publishers, pp. 219–234 (2001).Google Scholar
- Kaczorowski, G. and Garcia, M., Pharmacology of voltagegated and calcium-activated potassium channels. Curr. Opin. Investig. Drugs., 9, 2269–2280 (1999).Google Scholar
- Sivarao, D. V., Newberry, K., Langdon, S., Lee, A. V., Hewawasam, P., Plym, M., Signor, L., Myers, R., and Lodge, N., Effect of BMS-223131 a novel opener of large conductance Ca2+-activated K+ (maxi-K) channels on normal and stress aggravated colonic motility and visceral nociception. J. Pharmacol. Exp. Ther. Fast Forward., (2005).Google Scholar
- Suarez-Kurtz, G., Garcia, M., and Kaczorowski, G., Effects of charybdotoxin and iberiotoxin on the spontaneous motility and tonus of different guinea pig smooth muscle tissues. J. Pharmacol. Exp. Ther., 269, 439 (1991).Google Scholar