Abstract
Gamma-aminobutyric acid type A receptors (GABAAR) are allosterically modulated by the nonsteroidal anti-inflammatory drugs diflunisal and fenamates. The carboxyl group of these compounds is charged at physiological pH and therefore penetration of the compounds into the brain is low. In the present study we have transformed the carboxyl group of diflunisal and meclofenamate into non-ionizable functional groups and analyzed the effects of the modifications on stimulation of [3H]muscimol binding and on potentiation of γ-aminobutyric acid-induced displacement of 4′-ethenyl-4-n-[2,3-3H]propylbicycloorthobenzoate. N-Butylamide derivative of diflunisal modulated radioligand binding with equal or higher potency than the parent compound, while diflunisalamide showed reduced allosteric effect as compared to diflunisal. Amide derivative of meclofenamate equally affected radioligand binding parameters, while both diflunisal and meclofenamate methyl esters were less active than the parent compounds. Our study clearly demonstrates that an intact carboxyl group in diflunisal and meclofenamate is not indispensable for their positive GABAAR modulation. Further derivatization of the compound might yield compounds with higher selectivity for GABAARs that could be utilized in drug development.
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References
Olsen RW, Sieghart W (2008) International Union of Pharmacology. LXX. Subtypes of gamma-aminobutyric acid(A) receptors: classification on the basis of subunit composition, pharmacology, and function: update. Pharmacol Rev 60:243–260
Kozuska JL, Paulsen IM (2012) The Cys-loop pentameric ligand-gated ion channel receptors: 50 years on. Can J Physiol Pharmacol 90:771–782
Sieghart W (1995) Structure and pharmacology of gamma-aminobutyric acidA receptor subtypes. Pharmacol Rev 47:181–234
Woodward RM, Polenzani L, Miledi R (1994) Effects of fenamates and other nonsteroidal anti-inflammatory drugs on rat brain GABAA receptors expressed in Xenopus oocytes. J Pharmacol Exp Ther 268:806–817
Squires RF, Ai J, Witt MR, Kahnberg P, Saederup E, Sterner O, Nielsen M (1999) Honokiol and magnolol increase the number of [3H] muscimol binding sites threefold in rat forebrain membranes in vitro using a filtration assay, by allosterically increasing the affinities of low-affinity sites. Neurochem Res 24:1593–1602
Squires RF, Saederup E (2000) Additivities of compounds that increase the numbers of high affinity [3H]muscimol binding sites by different amounts define more than 9 GABA(A) receptor complexes in rat forebrain: implications for schizophrenia and clozapine research. Neurochem Res 25:1587–1601
Evoniuk G, Skolnick P (1988) Picrate and niflumate block anion modulation of radioligand binding to the gamma-aminobutyric acid/benzodiazepine receptor complex. Mol Pharmacol 34:837–842
Maksay G, Korpi ER, Uusi-Oukari M (1998) Bimodal action of furosemide on convulsant [3H]EBOB binding to cerebellar and cortical GABA(A) receptors. Neurochem Int 33:353–358
Sinkkonen ST, Mansikkamäki S, Möykkynen T, Lüddens H, Uusi-Oukari M, Korpi ER (2003) Receptor subtype-dependent positive and negative modulation of GABA(A) receptor function by niflumic acid, a nonsteroidal anti-inflammatory drug. Mol Pharmacol 64:753–763
Uusi-Oukari M, Maksay G (2006) Allosteric modulation of [3H]EBOB binding to GABAA receptors by diflunisal analogues. Neurochem Int 49:676–682
White MM, Aylwin M (1990) Niflumic and flufenamic acids are potent reversible blockers of Ca2(+)-activated Cl− channels in Xenopus oocytes. Mol Pharmacol 37:720–724
Halliwell RF, Thomas P, Patten D, James CH, Martinez-Torres A, Miledi R, Smart TG (1999) Subunit-selective modulation of GABAA receptors by the non-steroidal anti-inflammatory agent, mefenamic acid. Eur J Neurosci 11:2897–2905
Smith AJ, Oxley B, Malpas S, Pillai GV, Simpson PB (2004) Compounds exhibiting selective efficacy for different beta subunits of human recombinant gamma-aminobutyric acid A receptors. J Pharmacol Exp Ther 311:601–609
Coyne L, Su J, Patten D, Halliwell RF (2007) Characterization of the interaction between fenamates and hippocampal neuron GABA(A) receptors. Neurochem Int 51:440–446
Rae MG, Hilton J, Sharkey J (2012) Putative TRP channel antagonists, SKF 96365, flufenamic acid and 2-APB, are non-competitive antagonists at recombinant human α1β2γ2 GABA(A) receptors. Neurochem Int 60:543–554
Pygall SR, Griffiths PC, Wolf B, Timmins P, Melia CD (2011) Solution interactions of diclofenac sodium and meclofenamic acid sodium with hydroxypropyl methylcellulose (HPMC). Int J Pharm 405:55–62
Roberts LJ II, Morrow JD (2001) Analgesic-antipyretic and anti-inflammatory agents and drugs employed in the treatment of gout. In: Hardman JG, Limbird LE, Gilman AG (eds) The pharmacological basis of therapeutics, 10th edn. McGraw-Hill, New York, pp 687–731
Bannwarth B, Netter P, Pourel J, Royer RJ, Gaucher A (1989) Clinical pharmacokinetics of nonsteroidal anti-inflammatory drugs in the cerebrospinal fluid. Biomed Pharmacother 43:121–126
Fukuda M, Kitaichi K, Abe F, Fujimoto Y, Takagi K, Takagi K, Morishima T, Hasegawa T (2005) Altered brain penetration of diclofenac and mefenamic acid, but not acetaminophen, in Shiga-like toxin II-treated mice. J Pharmacol Sci 97:525–532
Squires RF, Saederup E (1999) Clozapine’s antipsychotic effects do not depend on blockade of 5-HT3 receptors. Neurochem Res 24:659–667
Ramerstorfer J, Furtmüller R, Sarto-Jackson I, Varagic Z, Sieghart W, Ernst M (2011) The GABAA receptor alpha + beta-interface: a novel target for subtype selective drugs. J Neurosci 31:870–877
Fernandez SP, Karim N, Mewett KN, Chebib M, Johnston GA, Hanrahan JR (2012) Flavan-3-ol esters: new agents for exploring modulatory sites on GABA(A) receptors. Br J Pharmacol 165:965–977
Li GD, Chiara DC, Sawyer GW, Husain SS, Olsen RW, Cohen JB (2006) Identification of a GABAA receptor anesthetic binding site at subunit interfaces by photolabeling with an etomidate analog. J Neurosci 26:11599–11605
Chiara DC, Dostalova Z, Jayakar SS, Zhou X, Miller KW, Cohen JB (2012) Mapping general anesthetic binding site(s) in human α1β3 γ-aminobutyric acid type A receptors with [3H]TDBzl-etomidate, a photoreactive etomidate analogue. Biochemistry 51:836–847
Wisden W, Laurie DJ, Monyer H, Seeburg PH (1992) The distribution of 13 GABAA receptor subunit mRNAs in the rat brain. I. Telencephalon, diencephalon, mesencephalon. J Neurosci 12:1040–1062
Thompson SA, Wheat L, Brown NA, Wingrove PB, Pillai GV, Whiting PJ, Adkins C, Woodward CH, Smith AJ, Simpson PB, Collins I, Wafford KA (2004) Salicylidene salicylhydrazide, a selective inhibitor of beta 1-containing GABAA receptors. Br J Pharmacol 142:97–106
Johnstone TB, Hogenkamp DJ, Coyne L, Su J, Halliwell RF, Tran MB, Yoshimura RF, Li WY, Wang J, Gee KW (2004) Modifying quinolone antibiotics yields new anxiolytics. Nat Med 10:31–32
Kalgutkar AS, Rowlinson SW, Crews BC, Marnett LJ (2002) Amide derivatives of meclofenamic acid as selective cyclooxygenase-2 inhibitors. Bioorg Med Chem Lett 12:521–524
Tabba HD, Abdel-Hamid ME, Suleiman MS, Al-Arab MM, Hasan MM, Abu-Lafi S, Najib NM (1989) Synthesis, identification and preliminary evaluation of esters and amide derivatives of diflunisal. Int J Pharm 54:57–63
Whitehouse MW, Rainsford KD (1980) Esterification of acidic anti-inflammatory drugs suppresses their gastrotoxicity without adversely affecting their anti-inflammatory activity in rats. J Pharm Pharmacol 32:795–796
Juszczak GR, Swiergiel AH (2009) Properties of gap junction blockers and their behavioural, cognitive and electrophysiological effects: animal and human studies. Prog Neuropsychopharmacol Biol Psychiatry 33:181–198
Farrugia G, Rae JL, Szurszewski JH (1993) Characterization of an outward potassium current in canine jejunal circular smooth muscle and its activation by fenamates. J Physiol 468:297–310
Lerma J, Martín del Río R (1992) Chloride transport blockers prevent N-methyl-D-aspartate receptor-channel complex activation. Mol Pharmacol 41:217–222
Peretz A, Degani-Katzav N, Talmon M, Danieli E, Gopin A, Malka E, Nachman R, Raz A, Shabat D, Attali B (2007) A tale of switched functions: from cyclooxygenase inhibition to M-channel modulation in new diphenylamine derivatives. PLoS One 2:e1332
Peretz A, Sheinin A, Yue C, Degani-Katzav N, Gibor G, Nachman R, Gopin A, Tam E, Shabat D, Yaari Y, Attali B (2007) Pre- and postsynaptic activation of M-channels by a novel opener dampens neuronal firing and transmitter release. J Neurophysiol 97:283–295
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This study was supported by grants from the Finnish Society of Sciences and Letters (MU-O), Oskar Öflund Foundation (MU-O) and the Turku University Foundation (MU-O).
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Uusi-Oukari, M., Vähätalo, L. & Liljeblad, A. Modifications of Diflunisal and Meclofenamate Carboxyl Groups Affect Their Allosteric Effects on GABAA Receptor Ligand Binding. Neurochem Res 39, 1183–1191 (2014). https://doi.org/10.1007/s11064-014-1351-x
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DOI: https://doi.org/10.1007/s11064-014-1351-x