3-Arylisothiazoloquinols As Potent Ligands for the Benzodiazepine Site of GABA_A Receptors

Jakob Nilsson, Elsebet Østergaard Nielsen, Tommy Liljefors, Mogens Nielsen, Olov Sterner

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DOI: 10.4236/jbise.2012.51001                

Abstract

3-Arylisothiazolo[5,4-b]quinolin-4(9H)-ones and 3-arylisoxazolo[5,4-b]quinolin-4(9H)-ones were synthesized and assayed for affinity for the benzodiazepine binding site of the GABAA receptors. While the 3-arylisothiazoloquinolin-4-ones were found to be potent ligands, with affinities (expressed as the affinity Ki value) down to 1 nM, the 3-arylisoxazoloquinolin-4-ones are less potent. This is suggested to depend on sterical repulsive interaction of the 3-arylisoxazoloquinolin-4-ones with the receptor essential volume of the binding site, and a higher electron density at the nitrogen in the azole ring (N-2) as well as the carbonyl oxygen in the isothiazoloquinolin-4-ones enabling them to interact stronger with hydrogen bond donor sites at the binding site.

Keywords

Isothiazolo[5, 4-b]quinolin-4(9H)-ones; Isoxazolo[5, 4-b]quinolin-4(9H)-ones; Benzodiazepine binding site; GABAA Receptors; GABAA Receptor Subtypes; Pharmacophore Model

Conflicts of Interest

The authors declare no conflicts of interest.

References

[1]	Sieghart, W. (2006) Structure, pharmacology, and function of GABAA receptor subtypes. Advances in Pharmacology, 54, 231-263. doi:10.1016/S1054-3589(06)54010-4
[2]	Johnston, G.A.R. (2005) GABAA receptor channel pharmacology. Current Pharmaceutical Design, 11, 1867-1885. doi:10.2174/1381612054021024
[3]	Olsen, R.W. and Sieghart, W. (2009) GABAA receptors: Subtypes provide diversity of function and pharmacology. Neuropharmacology, 56, 141-148. doi:10.1016/j.neuropharm.2008.07.045
[4]	Rudolph, U., Crestani, F., Benke, D., Brunig, I., Benson, J.A., Fritschy, J.M., Martin, J.R., Bluethmann, H. and Mohler, H. (1999) Benzodiazepine actions mediated by specific gamma-aminobutyric acidA, receptor subtypes. Nature, 401, 796-800. doi:10.1038/44579
[5]	Rudolph, U., Crestani, F. and M?hler, H. (2001) GABAA Receptor subtypes: Dissecting their pharmacological functions. Trends in Pharmacological Sciences, 22, 188-194. doi:10.1016/S0165-6147(00)01646-1
[6]	Zhang, W., Koehler, K.F., Zhang, P. and Cook, J.M. (1995) Development of a comprehensive pharmacophore model for the benzodiazepine receptor. Drug Design and Discovery, 12, 193-248.
[7]	Dekermendijan, K., Kahnberg, P., Witt, M., Sterner, O., Nielsen, M. and Liljefors, T. (1999) Structure-activity relationships and molecular modelling analysis of flavonoids binding to the benzodiazepine site of the rat brain GABAA receptor complex. Journal of Medicinal Chemistry, 42, 4343-4350. doi:10.1021/jm991010h
[8]	Kahnberg, P., Lager, E., Rosenberg, C., Schougaard, J., Camet, L., Sterner, O., ?stergaard Nielsen, E., Nielsen, M. and Liljefors, T. (2002) Refinement and evaluation of a pharmacophore model for flavone derivatives binding to the benzodiazepine site of the GABAA receptor. Journal of Medicinal Chemistry, 45, 4188-4201. doi:10.1021/jm020839k
[9]	Lager, E., Andersson, P., Nilsson, J., Pettersson, I., ?stergaard Nielsen, E., Nielsen, M., Sterner, O. and Liljefors, T. (2006) 4-Quinolone derivatives: High-affinity ligands at the benzodiazepine site of brain GABAA receptors. Synthesis, pharmacology and pharmacophore modelling. Journal of Medicinal Chemistry, 49, 2526-2533. doi:10.1021/jm058057p
[10]	Lager, E., Nilsson, J., ?stergaard Nielsen, E., Nielsen, M., Liljefors, T. and Sterner, O. (2008) Affinity of 3-acyl substituted 4-quinolones at the benzodiazepine site of GABAA receptors. Bioorganic and Medicinal Chemistry, 16, 6936-6948. doi:10.1016/j.bmc.2008.05.049
[11]	Nilsson, J., ?stergaard Nielsen, E., Liljefors, T., Nielsen, M. and Sterner, O. (2008) Azaflavones compared to flavones as ligands at the benzodiazepine site of brain GABAA receptors. Bioorganic and Medicinal Chemistry Letters, 18, 5713-5716. doi:10.1016/j.bmcl.2008.09.092
[12]	Yokoyama, N., Ritter, B. and Neubert, A.D. (1982) 2-Arylpyrazolo[4,3-c]quinolin-3-ones: A novel agonist, a partial agonist and an antagonist of benzodiazepines. Journal of Medicinal Chemistry, 25, 337-339. doi:10.1021/jm00346a002
[13]	Shindo, H., Takada, S., Murata, S., Eigyo, M. and Matsushita, A. (1989) Thienylpyrazoloquinolines with high affinity to benzodiazepine receptors: Continuous shift from inverse agonist to agonist properties depending on the size of the alkyl substituent. Journal of Medicinal Chemistry, 32, 1213-1217. doi:10.1021/jm00126a012
[14]	Allen, M.S., Hagen, T.J., Trudell, M.L., Codding, P.W., Skolnick, P. and Cook, J.M. (1988) Synthesis of novel 3-substituted-carbolines as benzodiazepine receptor ligands: Probing the benzodiazepine receptor pharmacophore. Journal of Medicinal Chemistry, 31, 1854-1861. doi:10.1021/jm00117a029
[15]	Trudell, M.L., Lifer, S.L., Tan, Y.C., Martin, M.J., Deng, L., Skolnick, P. and Cook, J.M. (1990) Synthesis of substituted 7,12-dihydropyrido[3,2-b:5,4-b’]diindoles: Rigid planar benzodiazepine receptor ligands with inverse agonist/antagonist properties. Journal of Medicinal Chemistry, 33, 2412-2420. doi:10.1021/jm00171a015
[16]	Albaugh, P., Marshall, L., Gregory, J., White, G., Hutchison, A., Ross, P., Gallagher, D., Tallman, J., Crago, M. and Cassella, J. (2002) Synthesis and biological evaluation of 7,8,9,10-tetrahydroimidazo[1,2-c]pyrido [3,4-e]pyrimdin-5(6H)-ones as functionally selective ligands of the benzodiazepine receptor site on the GABAA receptor. Journal of Medicinal Chemistry, 45, 5043-5051. doi:10.1021/jm0202019
[17]	He, X, Huang, Q., Ma, C., Yu, S., McKernan, R. and Cook, J.M. (2000) Pharmacophore/receptor models for GABAA/BzR ?2?3?2, ?3?3?2 and ?4?3?2 recombinant subtypes. Including volume analysis and comparison to ?1?3?2, ?5?3?2 and ?6?3?2 subtypes. Drug Design and Discovery, 17, 131-171.
[18]	Kahnberg, P., Howard, M.H., Liljefors, T., Nielsen, M., ?stergaard Nielsen, E., Sterner, O. and Pettersson, I. (2004) The use of a pharmacophore model for identification of novel ligands for the benzodiazepine binding site of the GABAA receptor. Journal of Molecular Graphics and Modelling, 23, 253-261. doi:10.1016/j.jmgm.2004.06.003
[19]	Matsuoka, M., Segawa, J., Makita, Y., Ohmachi, S., Kashima, T., Nakamura, K.-I., Hattori, M., Kitano, M. and Kise, M. (1997) Studies on pyridonecarboxylic acids. V. A practical synthesis of ethyl 6,7-difluoro-1-methyl-4-oxo-4H-[1,3]thiazeto[3,2-a]quinoline-3-carboxylate, a key intermediate for the new tricyclic quinolone, prulifloxacin (NM441) and versatile new syntheses of the 2-thioquinoline skeleton. Journal of Heterocyclic Chemistry, 34, 1773-1779. doi:10.1002/jhet.5570340622
[20]	Choi, J.H., Choi, E.B. and Pak, C.S. (2003) Isothiazole ring formation with substituted 2-alkylthio-3-acyl-4-quinolinone using O-(mesitylenesulfonyl)-hydroxylamine (MSH). Synlett, 2, 166-172.
[21]	Chimichi, S., Boccalini, M. and Matteucci, A. (2007) Unambiguous structure elucidation of the reaction products of 3-acyl-4-methoxy-1-methylquinolinones with hydroxylamine via NMR spectroscopy. Tetrahedron, 63, 11656-11660. doi:10.1016/j.tet.2007.08.108
[22]	Yoo, K.H., Choi, E.B., Lee, H.K., Yeon, G.H., Yang, H.C. and Pak, C.S. (2006) Beckmann rearrangement using indium(III) chloride: Synthesis of substituted oxazoloquinolines from the corresponding ketoximes of 3-acyl-1H-quinolin-4-ones. Synthesis, 10, 1599-1612.