Exploring thienothiadiazine dioxides as isosteric analogues of benzo-and pyridothiadiazine dioxides in the search of new AMPA and kainate receptor positive allosteric modulators
Francotte, Pierre; Bay, Yasmin; Goffin, Ericet al.
2023 • In European Journal of Medicinal Chemistry, 264, p. 116036
Ionotropic glutamate receptors Positive allosteric modulators thieno[3; 2-e]-1; 2; 4-thiadiazine 1; 1-dioxides 1; 4-Benzothiadiazine 1; 1-dioxides X-ray crystallography Calcium-sensitive fluorescence-based assay; Organic Chemistry; Drug Discovery; Pharmacology; General Medicine
Abstract :
[en] The synthesis and biological evaluation on AMPA and kainate receptors of new examples of 3,4-dihydro-2H-1,2,4-thieno[3,2-e]-1,2,4-thiadiazine 1,1-dioxides is described. The introduction of a cyclopropyl chain instead of an ethyl chain at the 4-position of the thiadiazine ring was found to dramatically improve the potentiator activity on AMPA receptors, with compound 32 (BPAM395) expressing in vitro activity on AMPARs (EC2x = 0.24 μM) close to that of the reference 4-cyclopropyl-substituted benzothiadiazine dioxide 10 (BPAM344). Interestingly, the 4-allyl-substituted thienothiadiazine dioxide 27 (BPAM307) emerged as the most promising compound on kainate receptors being a more effective potentiator than the 4-cyclopropyl-substituted thienothiadiazine dioxide 32 and supporting the view that the 4-allyl substitution of the thiadiazine ring could be more favorable than the 4-cyclopropyl substitution to induce marked activity on kainate receptors versus AMPA receptors. The thieno-analogue 36 (BPAM279) of the clinically tested S18986 (11) was selected for in vivo evaluation in mice as a cognitive enhancer due to a safer profile than 32 after massive per os drug administration. Compound 36 was found to increase the cognition performance in mice at low doses (1 mg/kg) per os suggesting that the compound was well absorbed after oral administration and able to reach the central nervous system. Finally, compound 32 was selected for co-crystallization with the GluA2-LBD (L504Y,N775S) and glutamate to examine the binding mode of thienothiadiazine dioxides within the allosteric binding site of the AMPA receptor. At the allosteric site, this compound established similar interactions as the previously reported BTD-type AMPA receptor modulators.
Disciplines :
Pharmacy, pharmacology & toxicology Chemistry
Author, co-author :
Francotte, Pierre ; Université de Liège - ULiège > Département de pharmacie > Chimie pharmaceutique
Bay, Yasmin; Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
Goffin, Eric ; Université de Liège - ULiège > Département de pharmacie > Chimie pharmaceutique
Colson, Thomas ; Université de Liège - ULiège > Département de pharmacie > Chimie pharmaceutique
Lesenfants, Cindy ; Université de Liège - ULiège > Département de pharmacie > Chimie pharmaceutique
Dorosz, Jerzy; Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
Laulumaa, Saara; Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
Fraikin, Pierre ; Université de Liège - ULiège > Département de pharmacie > Chimie pharmaceutique
De Tullio, Pascal ; Université de Liège - ULiège > Département de pharmacie > Chimie pharmaceutique
Beaufour, Caroline; Institut de Recherches et Développement Servier Paris-Saclay, Gif-sur-Yvette, France
Botez, Iuliana; Institut de Recherches et Développement Servier Paris-Saclay, Gif-sur-Yvette, France
Pickering, Darryl; Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
Frydenvang, Karla; Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
Danober, Laurence; Institut de Recherches et Développement Servier Paris-Saclay, Gif-sur-Yvette, France
Skov Kristensen, Anders; Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
Sandholm Kastrup, Jette; Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
Pirotte, Bernard ; Université de Liège - ULiège > Département de pharmacie
Exploring thienothiadiazine dioxides as isosteric analogues of benzo-and pyridothiadiazine dioxides in the search of new AMPA and kainate receptor positive allosteric modulators
Frydenvang, K., Pickering, D.S., Kastrup, J.S., Structural basis for positive allosteric modulation of AMPA and kainate receptors. J. Physiol. 600 (2022), 181–200, 10.1113/JP280873.
Chang, P.K.Y., Verbich, D., McKinney, R.A., AMPA receptors as drug targets in neurological disease – advantages, caveats, and future outlook. Eur. J. Neurosci. 35 (2012), 1908–1916, 10.1111/j.1460-9568.2012.08165.x.
Pirotte, B., Francotte, P., Goffin, E., de Tullio, P., AMPA receptor positive allosteric modulators: a patent review. Expert Opin. Ther. Pat. 13 (2013), 615–628, 10.1517/13543776.2013.770840.
Giralt, A., Gomez-Climent, M.A., Alcala, R., Bretin, S., Bertrand, D., Delgado-Garcia, J.M., Perez-Navarro, E., Alberch, J., Gruart, A., The AMPA receptor positive allosteric modulator S 47445 rescues in vivo CA3-CA1 long-term potentiation and structural synaptic changes in old mice. Neuropharmacology 123 (2017), 395–409, 10.1016/j.neuropharm.2017.06.009.
Brogi, S., Campiani, G., Brindisi, M., Butini, S., Allosteric modulation of ionotropic glutamate receptors: an outlook on new therapeutic approaches to treat central nervous system disorders. ACS Med. Chem. Lett. 10 (2019), 228–236, 10.1021/acsmedchemlett.8b00450.
Kadriu, B., Musazzi, L., Johnston, J.N., Kalynchuk, L.E., Caruncho, H.J., Popoli, M., Zarate, C.A., Positive AMPA receptor modulation in the treatment of neuropsychiatric disorders: a long and winding road. Drug Discov. Today 26 (2021), 2816–2838, 10.1016/j.drudis.2021.07.027.
Jourdi, H., Hsu, Y.T., Zhou, M., Qin, Q., Bi, X., Baudry, M., Positive AMPA receptor modulation rapidly stimulates BDNF release and increases dendritic mRNA translation. J. Neurosci. 29 (2009), 8688–8697, 10.1523/JNEUROSCI.6078-08.2009.
Lerma, J., Marques, J.M., Kainate receptors in health and disease. Neuron 80 (2013), 292–311, 10.1016/j.neuron.2013.09.045.
Begni, S., Popoli, M., Moraschi, S., Bignotti, S., Tura, G.B., Gennarelli, M., Association between the ionotropic glutamate receptor kainate 3 (GRIK3) ser310ala polymorphism and schizophrenia. Mol. Psychiatr. 7 (2002), 416–418, 10.1038/sj.mp.4000987 2002.
Schiffer, H.H., Heinemann, S.F., Association of the human kainate receptor GluR7 gene (GRIK3) with recurrent major depressive disorder. Am. J. Med. Genet. B. Neuropsychiatr. Genet. 144B (2007), 20–26, 10.1002/ajmg.b.30374 2007.
Palmer, C.L., Cotton, L., Henley, J.M., The molecular pharmacology and cell biology of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors. Pharmacol. Rev. 57 (2005), 253–277, 10.1124/pr.57.2.7.
Mansour, M., Nagarajan, N., Nehring, R.B., Clements, J.D., Rosenmund, C., Heteromeric AMPA receptors assemble with a preferred subunit stoichiometry and spatial arrangement. Neuron 32 (2001), 841–853, 10.1016/s0896-6273(01)00520-7.
Contractor, A., Mulle, C., Swanson, G.T., Kainate receptors coming of age: milestones of two decades of research. Trends Neurosci. 34 (2011), 154–163, 10.1016/j.tins.2010.12.002 2011.
Armstrong, N., Gouaux, E., Mechanisms for activation and antagonism of an AMPA-sensitive glutamate receptor: crystal structures of the GluR2 ligand binding core. Neuron 28 (2000), 165–181, 10.1016/s0896-6273(00)00094-5.
Sobolevsky, A.I., Rosconi, M.P., Gouaux, E., X-ray structure, symmetry and mechanism of an AMPA-subtype glutamate receptor. Nature 462 (2009), 745–756, 10.1038/nature08624.
Ptak, C.P., Ahmed, A.H., Oswald, R.E., Probing the allosteric modulator binding site of GluR2 with thiazide derivatives. Biochemistry 48 (2009), 8594–8602, 10.1021/bi901127s.
Kaae, B.H., Harpsøe, K., Kastrup, J.S.J., Sanz, A.C., Pickering, D.S., Metzler, B., Clausen, R.P., Gajhede, M., Sauerberg, P., Liljefors, T., Madsen, U., Structural proof of a dimeric positive modulator bridging two identical AMPA receptor-binding sites. Chem. Biol. 14 (2007), 1294–1303, 10.1016/j.chembiol.2007.10.012.
Timm, D.E., Benveniste, M., Weeks, A.M., Nisenbaum, E.S., Partin, K.M., Structural and functional analysis of two new positive allosteric modulators of GluA2 desensitization and deactivation. Mol. Pharmacol. 80 (2011), 267–280, 10.1124/mol.110.070243.
Larsen, A.P., Fièvre, S., Frydenvang, K., Francotte, P., Pirotte, B., Kastrup, J.S., Mulle, C., Identification and structure-function study of positive allosteric modulators of kainate receptors. Mol. Pharmacol. 91 (2017), 576–585, 10.1124/mol.116.107599.
Francotte, P., de Tullio, P., Goffin, E., Dintilhac, G., Graindorge, E., Fraikin, P., Lestage, P., Danober, L., Thomas, J.Y., Caignard, D.H., Pirotte, B., Design, synthesis, and pharmacology of novel 7-substituted 3,4-dihydro-2H-1,2,4-benzothiadiazine 1,1-dioxides as positive allosteric modulators of AMPA receptors. J. Med. Chem. 50 (2007), 3153–3157, 10.1021/jm070120i.
Francotte, P., de Tullio, P., Podona, T., Diouf, O., Fraikin, P., Lestage, P., Danober, L., Thomas, J.Y., Caignard, D.H., Pirotte, B., Synthesis and pharmacological evaluation of a second generation of pyridothiadiazine 1,1-dioxides acting as AMPA potentiators. Bioorg. Med. Chem. 16 (2008), 9948–9956, 10.1016/j.bmc.2008.10.036.
Francotte, P., Goffin, E., Fraikin, P., Lestage, P., Van Heugen, J.C., Gillotin, F., Danober, L., Thomas, J.Y., Chiap, P., Caignard, D.H., Pirotte, B., de Tullio, P., New fluorinated 1,2,4-benzothiadiazine 1,1-dioxides: discovery of an orally active cognitive enhancer acting through potentiation of the 2-amino-3-(3-hydroxy-5-methylisoxazol-4-yl)propionic acid receptors. J. Med. Chem. 53 (2010), 1700–1711, 10.1021/jm901495t.
Krintel, C., Frydenvang, K., Olsen, L., Kristensen, M.T., de Barrios, O., Naur, P., Francotte, P., Pirotte, B., Gajhede, M., Kastrup, J.S., Thermodynamics and structural analysis of positive allosteric modulation of the ionotropic glutamate receptor GluA2. Biochem. J. 441 (2012), 173–178, 10.1042/BJ20111221.
Francotte, P., Goffin, E., Fraikin, P., Graindorge, E., Lestage, P., Danober, L., Challal, S., Rogez, N., Nosjean, O., Caignard, D.H., Pirotte, B., de Tullio, P., Development of thiophenic analogues of benzothiadiazine dioxides as new powerful potentiators of 2-amino-3-(3-hydroxy-5-methylisoxazol-4-yl)propionic acid (AMPA) receptors. J. Med. Chem. 56 (2013), 7838–7850, 10.1021/jm400676g.
Nørholm, A.B., Francotte, P., Olsen, L., Krintel, C., Frydenvang, K., Goffin, E., Challal, S., Danober, L., Botez-Pop, I., Lestage, P., Pirotte, B., Kastrup, J.S., Synthesis, pharmacological and structural characterization, and thermodynamic aspects of GluA2-positive allosteric modulators with a 3,4-dihydro-2H-1,2,4-benzothiadiazine 1,1-dioxide scaffold. J. Med. Chem. 56 (2013), 8736–8745, 10.1021/jm4012092.
Francotte, P., Nørholm, A.B., Deva, T., Olsen, L., Frydenvang, K., Goffin, E., Fraikin, P., de Tullio, P., Challal, S., Thomas, J.Y., Iop, F., Louis, C., Botez-Pop, I., Lestage, P., Danober, L., Kastrup, J.S., Pirotte, B., Positive allosteric modulators of 2-amino-3-(3-hydroxy-5-methylisoxazol-4-yl)propionic acid receptors belonging to 4-cyclopropyl-3,4-dihydro-2H-1,2,4-pyridothiadiazine dioxides and diversely chloro-substituted 4-cyclopropyl-3,4-dihydro-2H-1,2,4-benzothiadiazine 1,1-dioxides. J. Med. Chem. 57 (2014), 9539–9553, 10.1021/jm501268r.
Nørholm, A.B., Francotte, P., Goffin, E., Botez, I., Danober, L., Lestage, P., Pirotte, B., Kastrup, J.S., Olsen, L., Oostenbrink, C., Thermodynamic characterization of new positive allosteric modulators binding to the glutamate receptor A2 ligand-binding domain: combining experimental and computational methods unravels differences in driving forces. J. Chem. Inf. Model. 54 (2014), 3404–3416, 10.1021/ci500559b.
Larsen, A.P., Francotte, P., Frydenvang, K., Tapken, D., Goffin, E., Fraikin, P., Caignard, D.H., Lestage, P., Danober, L., Pirotte, B., Kastrup, J.S., Synthesis and pharmacology of mono-, di-, and trialkyl-substituted 7-chloro-3,4-dihydro-2H-1,2,4-benzothiadiazine 1,1-dioxides combined with X-ray structure analysis to understand the unexpected structure-activity relationship at AMPA receptors. ACS Chem. Neurosci. 7 (2016), 378–390, 10.1021/acschemneuro.5b00318.
Krintel, C., Francotte, P., Pickering, D.S., Juknaitė, L., Pøhlsgaard, J., Olsen, L., Frydenvang, K., Goffin, E., Pirotte, B., Kastrup Js, J.S., Enthalpy-entropy compensation in the binding of modulators at ionotropic glutamate receptor GluA2. Biophys. J. 110 (2016), 2397–2406, 10.1016/j.bpj.2016.04.032.
Goffin, E., Drapier, T., Larsen, A.P., Geubelle, P., Ptak, C.P., Laulumaa, S., Rovinskaja, K., Gilissen, J., de Tullio, P., Olsen, L., Frydenvang, K., Pirotte, B., Hanson, J., Oswald, R.E., Kastrup, J.S., Francotte, P., 7-Phenoxy-substituted 3,4-dihydro-2H-1,2,4-benzothiadiazine 1,1-dioxides as positive allosteric modulators of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors with nanomolar potency. J. Med. Chem. 61 (2018), 251–264, 10.1021/acs.jmedchem.7b01323.
Drapier, T., Geubelle, P., Bouckaert, C., Nielsen, L., Laulumaa, S., Goffin, E., Dilly, S., Francotte, P., Hanson, J., Pochet, L., Kastrup, J.S., Pirotte, B., Enhancing action of positive allosteric modulators through the design of dimeric compounds. J. Med. Chem. 61 (2018), 5279–5291, 10.1021/acs.jmedchem.8b00250.
Etsè, K.S., Dorosz, J., McLain Christensen, K., Thomas, J.Y., Botez Pop, I., Goffin, E., Colson, T., Lestage, P., Danober, L., Pirotte, B., Kastrup, J.S., Francotte, P., Development of thiochroman dioxide analogues of benzothiadiazine dioxides as new positive allosteric modulators of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors. ACS Chem. Neurosci. 12 (2021), 2679–2692, 10.1021/acschemneuro.1c00255.
Bernard, K., Danober, L., Thomas, J.-Y., Lebrun, C., Munoz, C., Cordi, A., Desos, P., Lestage, P., Morain, P., S 18986: a positive allosteric modulator of AMPA-type glutamate receptors pharmacological profile of a novel cognitive enhancer. CNS Neurosci. Ther. 16 (2010), e193–e212, 10.1111/j.1755-5949.2009.00088.x.
https://classic.clinicaltrials.gov/ct2/show/NCT00202540 Efficacy and Safety of S18986 in the Treatment of Mild Cognitive Impairment Patients.
Goffin, E., Fraikin, P., Abboud, D., de Tullio, P., Beaufour, C., Botez, I., Hanson, J., Danober, L., Francotte, P., Pirotte, B., New insights in the development of positive allosteric modulators of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors belonging to 3,4-dihydro-2H-1,2,4-benzothiadiazine 1,1-dioxides: introduction of (mono/difluoro)methyl groups at the 2-position of the thiadiazine ring. Eur. J. Med. Chem., 250, 2023, 115221, 10.1016/j.ejmech.2023.115221.
Yoshida, Y., Umezu, K., Hamada, Y., Atsumi, N., Tabuchi, F., Practical synthesis of N-cyclopropylanilines via direct condensation of anilines with [(1-ethoxycyclopropyl)oxy]trimethylsilane. Synlett 14 (2003), 2139–2142, 10.1055/s-2003-42072.
Burnashev, N., Zhou, Z., Neher, E., Sakmann, B., Fractional calcium currents through recombinant GluR channels of the NMDA, AMPA and kainate receptor subtypes. J. Physiol. 485 (1995), 403–418 10.1113/jphysiol.1995.sp.020738.
Sommer, B., Keinänen, K., Verdoorn, T.A., Wisden, W., Burnashev, N., Herb, A., Köhler, M., Takagi, T., Sakmann, B., Seeburg, P.H., Flip and flop: a cell-specific functional switch in glutamate-operated channels of the CNS. Science 249 (1990), 1580–1585 10.1126/science.1699275.
Ward, S.E., Harries, M.H., Aldegheri, L., Bradford, A.M., Ballini, E., Dawson, L., Lacroix, L., Pardoe, J., Starr, K., Weil, A., Waters, K., Atack, J.R., Woolley, M., Pharmacological characterisation of MDI-222, a novel AMPA receptor positive allosteric modulator with an improved safety profile. J. Psychopharmacol. 34 (2020), 93–102, 10.1177/0269881119872198.
Shaffer, C.L., Hurst, R.S., Scialis, R.J., Osgood, S.M., Bryce, D.K., Hoffmann, W.E., Lazzaro, J.T., Hanks, A.N., Lotarski, S., Weber, M.L., Liu, J., Menniti, F.S., Schmidt, C.J., Hajós, M., Positive allosteric modulation of AMPA receptors from efficacy to toxicity: the interspecies exposure-response continuum of the novel potentiator PF-4778574. J. Pharmacol. Exp. Therapeut. 347 (2013), 212–224, 10.1124/jpet.113.204735.
Bliss, T.V.P., Collingridge, G.L., A synaptic model of memory: long-term potentiation in the hippocampus. Nature 361 (1993), 31–39, 10.1038/361031a0.
Whitlock, J.R., Heynen, A.J., Shuler, M.G., Bear, M.F., Learning induces long-term potentiation in the hippocampus. Science 313 (2006), 1093–1097, 10.1126/science.1128134.
Ennaceur, A., Delacour, J., A new one-trial test for neuro-biological studies of memory in rats. 1: behavioral data, Behav. Brain Res. 31 (1988), 47–59, 10.1016/0166-4328(88)90157-x.
Sun, Y., Olson, R., Horning, M., Armstrong, N., Mayer, M., Gouaux, E., Mechanism of glutamate receptor desensitization. Nature 417 (2002), 245–253, 10.1038/417245a.
Pøhlsgaard, J., Frydenvang, K., Madsen, U., Kastrup, J.S., Lessons from more than 80 structures of the GluA2 ligand-binding domain in complex with agonists, antagonists and allosteric modulators. Neuropharmacology 60 (2011), 135–150, 10.1016/j.neuropharm.2010.08.004.
Caminati, W., Melandri, S., Maris, A., Ottaviani, P., Relative strengths of the O-H⋯Cl and O-H⋯F hydrogen bonds. Angew. Chem. Int. Ed. 45 (2006), 2438–2442 10.1002/anie.200504486.
Chałupnik, P., Vialko, A., Pickering, D.S., Hinkkanen, M., Donbosco, S., Møller, T.C., Jensen, A.A., Nielsen, B., Bay, Y., Kristensen, A.S., Johansen, T.N., Łątka, K., Bajda, M., Szymańska, E., Discovery of the first highly selective antagonist of the GluK3 kainate receptor subtype. Int. J. Mol. Sci., 23, 2022, 8797, 10.3390/ijms23158797.
Keeney, A.J., Hogg, S., Marsden, C.A., Alterations in core body temperature, locomotor activity, and corticosterone following acute and repeated social defeat of male NMRI mice. Physiol. Behav. 74 (2001), 177–184, 10.1016/s0031-9384(01)00541-8.
Jacobson, L.H., Cryan, J.F., Differential sensitivity to the motor and hypothermic effects of the GABAB receptor agonist baclofen in various mouse strains. Psychopharmacology (Berl) 179 (2005), 688–699, 10.1007/s00213-004-2086-1.
Kristensen, L.V., Sandager-Nielsen, K., Hansen, H.H., Kv7 (KCNQ) channel openers induce hypothermia in the mouse. Neurosci. Lett. 488 (2011), 178–182, 10.1016/j.neulet.2010.11.024.
Krintel, C., Frydenvang, K., Ceravalls de Rabassa, A., Kaern, A.M., Gajhede, M., Pickering, D.S., Kastrup, J.S., L-Asp is a useful tool in the purification of the ionotropic glutamate receptor A2 ligand-binding domain. FEBS J. 281 (2014), 2422–2430, 10.1111/febs.12795.
Kabsch, W., Xds, Acta Crystallogr. D Biol. Crystallogr. 66 (2010), 125–132, 10.1107/S0907444909047337.
Winn, M.D., Ballard, C.C., Cowtan, K.D., Dodson, E.J., Emsley, P., Evans, P.R., Keegan, R.M., Krissinel, E.B., Leslie, A.G., McCoy, A., McNicholas, S.J., Murshudov, G.N., Pannu, N.S., Potterton, E.A., Powell, H.R., Read, R.J., Vagin, A., Wilson, K.S., Overview of the CCP4 suite and current developments. Acta Crystallogr. D Biol. Crystallogr. 67 (2011), 235–242, 10.1107/S0907444910045749.
Moriarty, N.W., Grosse-Kunstleve, R.W., Adams, P.D., Electronic Ligand Builder and Optimization Workbench (eLBOW): a tool for ligand coordinate and restraint generation. Acta Crystallogr. D Biol. Crystallogr. 65 (2009), 1074–1080, 10.1107/S0907444909029436 2009.
Emsley, P., Lohkamp, B., Scott, W.G., Cowtan, K., Features and development of Coot. Acta Crystallogr. D Biol. Crystallogr. 66 (2010), 486–501, 10.1107/S0907444910007493.
Hayward, S., Berendsen, H.J., Systematic analysis of domain motions in proteins from conformational change; new results on citrate synthase and T4 lysozyme. Proteins 30 (1998), 144–154, 10.1002/(SICI)1097-0134(19980201)30:2<144::AID-PROT4>3.0.CO;2-N.
