Design and synthesis of hydroxy-alkynoic acids and their methyl esters as novel activators of BK channels

Bioorganic and Medicinal Chemistry Letters

Volumn 18, Issue 11, 2008, Pages 3427-3430

  Patil, Shivaputra ^a   Bukiya, Anna N ^b   Li, Wei ^a   Dopico, Alejandro M ^b   Miller, Duane ^a  

^a UNIVERSITY OF TENNESSEE HEALTH SCIENCE CENTER   (United States)

^b UNIVERSITY OF TENNESSEE COLLEGE OF MEDICINE   (United States)

Author keywords

Activators; Hydroxy alkynoic acid; Lithocholic acid; MaxiK channel; Smooth muscle

Indexed keywords

CHOLANE DERIVATIVE; ESTER DERIVATIVE; HYDROXY ALKYNOIC ACID METHYL ESTER; LARGE CONDUCTANCE CALCIUM ACTIVATED POTASSIUM CHANNEL; LITHOCHOLIC ACID; STEROID;

ANIMAL CELL; ARTERY DILATATION; ARTICLE; BRAIN ARTERY; BRAIN BLOOD VESSEL; CONTROLLED STUDY; DRUG DESIGN; DRUG SYNTHESIS; MUSCLE CELL; NONHUMAN; RAT; SMOOTH MUSCLE; VASCULAR SMOOTH MUSCLE;

ANIMALS; HYDROXY ACIDS; LARGE-CONDUCTANCE CALCIUM-ACTIVATED POTASSIUM CHANNELS; LITHOCHOLIC ACID; MOLECULAR CONFORMATION; MOLECULAR STRUCTURE; MUSCLE CELLS; MUSCLE, SMOOTH; RATS;

RATTUS;

EID: 44149125294     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.bmcl.2008.03.080     Document Type: Article

References (17)

1. Orio P., Rojas P., Ferreira G., and Latorre R. News Physiol. Sci. 17 (2002) 156
2. Brayden J.E., and Nelson M.T. Science 256 (1992) 532
3. Jaggar J.H., Wellman G.C., Heppner T.J., Porter V.A., Perez G.J., Gollasch M., Kleppisch T., Rubart M., Stevenson A.S., Lederer W.J., Knot H.J., Bonev A.D., and Nelson M.T. Acta Physiol. Scand. 164 (1998) 577
4. Dopico A.M., Walsh Jr. J.V., and Singer J.J. J. Gen. Physiol. 119 (2002) 251
5. Bukiya A.N., Liu J., Toro L., and Dopico A.M. Mol. Pharmacol. 72 (2007) 359
6. Maruyama T., Miyamoto Y., Nakamura T., Tamai Y., Okada H., Sugiyama E., Nakamura T., Itadani H., and Tanaka K. Biochem. Biophys. Res. Commun. 298 (2002) 714
7. Makishima M., Lu T.T., Xie W., Whitfield G.K., Domoto H., Evans R.M., Haussler M.R., and Mangelsdorf D.J. Science 296 (2002) 1313
8. Gerasimenko J.V., Flowerdew S.E., Voronina S.G., Sukhomlin T.K., Tepikin A.V., Petersen O.H., and Gerasimenko O.V. J. Biol. Chem. 281 (2006) 40154
9. Modica S., and Moschetta A. FEBS Lett. 580 (2006) 5492
10. Bukiya, A. N.; Vaithianathan, T.; Toro, L.; Dopico, A. M. FEBS Lett., in press.
11. Carey, M. C. Physical-chemical properties of bile acids and their salts. In Sterols and Bile Acids; Danielsson, H., Sjovall, J., Eds., 1985, p 345.
12. Cobbledick R.E., and Einstein F.W. Acta Cryst. B36 (1980) 287
13. 4, and solvents were evaporated under reduced pressure. Residue was taken to the next step without further purification. The crude residue from the above reaction was refluxed nearly 2 h under methanol (50 ml) in the presence of a catalytic amount of sulfuric acid. Solvents were reduced to half under reduced pressure and extracted with ethyl acetate. The organic layer was dried and evaporated to dryness. The crude residue was purified 9:1 ethyl acetate/hexanes (pure methyl esters were re-hydrolyzed using NaOH to get pure acids).
14. - as the main anion was used as ground electrode. After excision from the cell, the membrane patch was exposed to a stream of bath solution containing each agent at final concentration. Solutions were applied onto the patches using an automated pressurized drug-delivery system via a micropipette tip with an internal diameter of 100 μm. Experiments were carried out at room temperature (21 °C). Currents were recorded using an EPC8 amplifier at 1 kHz using a low-pass, eight-pole Bessel filter 902LPF. Data were digitized at 5 kHz using a Digidata 1320A A/D converter and analyzed with pCLAMP 8.0.
15. Knot H.J., and Nelson M. J. Physiol. 508 (1998) 199
16. Perez G.J., Bonev A.D., and Nelson M.T. Am. J. Physiol. Cell Physiol. 281 (2001) C1769
17. Dopico A.M., Lemos J.R., and Treistman S.N. Mol. Pharmacol. 49 (1996) 40