Enantioselective synthesis of a pyrrolo-benzothiadiazine derivative S 18986, a new AMPA receptor positive modulator

Desos, Patrice; Serkiz, Bernard; Morain, Philippe; Lepagnol, J.; Cordi, Alex

doi:10.1016/s0960-894x(96)00547-1

Cited by 41 publications

(25 citation statements)

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“…Other compounds have recently been described that also exhibit greatly improved potency for the AMPA receptor. Some of them are structurally very similar to the compounds described here, such as S18986 (Desos et al, 1996) and the pyridothiadiazines (Pirotte et al, 1998). Others do not contain the characteristic bicyclic core but have a sulfonamide embedded in an elongated molecular structure, such as PEPA (Sekiguchi et al, 1997) and LY395153 and related compounds (Ornstein et al, 2000), the latter of which exhibited submicromolar EC 50 values in various physiological tests.…”

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confidence: 55%

“…However, IDRA-21 has modest potency, with concentrations above 200 M typically needed to enhance excitatory transmission in hippocampal slices (Arai et al, 1996a). Our efforts as well as those of others (Desos et al, 1996;Pirotte et al, 1998) have therefore been directed at finding analogs that have higher potency yet maintain effect profiles that are suitable for behavioral applications. In the present project, we systematically modified substituents at various locations around the benzothiadiazide core of IDRA-21 and measured the effects on various aspects of AMPA receptor operation.…”

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confidence: 99%

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Effects of 5′-Alkyl-Benzothiadiazides on (R,S)-α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid (AMPA) Receptor Biophysics and Synaptic Responses

Arai

Xia²,

Kessler³

et al. 2002

Mol Pharmacol

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Alkyl-substituted benzothiadiazides (BTDs) were tested for their effects on (R,S)-␣-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-type glutamate receptors. In excised patches, the 5Ј-ethyl derivative "D1" blocked the desensitization of AMPA receptor currents during prolonged application of glutamate (EC 50 , 36 M), and it slowed deactivation of responses elicited by 1-ms glutamate pulses greater than 10-fold. [3 H]Fluorowillardiine binding to rat synaptic membranes was increased by D1 by a factor of 3.6 (EC 50 , 17 M) with a Hill coefficient near 2. In hippocampal slices, the compound reversibly increased excitatory postsynaptic currents and field excitatory postsynaptic potentials (EPSPs) with thresholds around 10 M. The size of the alkyl substituent influenced both the potency and nature of the drug effect on synaptic currents: 5Ј-methyl compounds had a 2-fold greater effect on response amplitude than on response duration, whereas 5Ј-ethyl compounds like D1 caused greater increases in duration than amplitude. In tests with recombinantly expressed AMPA receptor subunits, D1 preferred the glutamate receptor (GluR) subunit GluR4 flip (0.64 M) over GluR4 flop (5.3 M); similar affinities but with smaller flip-flop differences were obtained for GluR1 through 3. These results show that D1 and congeners are significantly more potent than the parent compound IDRA-21 and that they differ in two fundamental aspects from cyclothiazide, the most widely studied BTD: 1) D1 markedly increases the agonist affinity of AMPA receptors and 2) it has immediate and large effects on field EPSPs. The large gain in potency conferred by alkyl substitution suggests that the 5Ј substituent is in intimate contact with the receptor, with the size of the substituent determining the way in which receptor kinetics is changed.

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confidence: 55%

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confidence: 99%

Effects of 5′-Alkyl-Benzothiadiazides on (R,S)-α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid (AMPA) Receptor Biophysics and Synaptic Responses

Arai

Xia²,

Kessler³

et al. 2002

Mol Pharmacol

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“…To date, LY451395 has been tested in a phase II trial for efficacy in patients with mild to moderate Alzheimer's disease but failed to improve cognitive function assessed by ADAS-Cog (Chappell et al, 2007). S18986 (Desos et al, 1996) represents a class of compounds with impact on AMPA receptor function intermediate between that of CX516 and LY451395. S18986, and N-((3R,4S)-3-(4-(5-cyanothiophen-2-yl)phenyl)-tetrahydro-2H-pyran-4-yl)propane-2-sulfonamide (PF-4778574) are all under consideration for clinical development.…”

Section: E ␣-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid and mentioning

confidence: 99%

Glutamate Receptor Ion Channels: Structure, Regulation, and Function

et al. 2010

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“…Since we have previously shown that cyclothiazide and CX614 do not appear to interact in a fully competitive way, the lack of interaction of CX516 with either of these drugs augments further the complexity of the pharmacology of these up-modulators. It also remains to be explored how newer sulfonamide-type modulators such as PEPA (Sekiguchi et al, 1997), S18986 (Desos et al, 1996), biarylsulfonamides (Ornstein et al, 2000;Linden et al, 2001), and D1 Phillips et al, 2002) relate to these subcategories. It will also be of interest to study in the paradigms used here newer analogs of CX516 that are functionally similar yet possess micromolar affinities.…”

Section: Two Subfamilies Of Benzamide Ampa Receptor Modulators 1083mentioning

confidence: 99%

Benzamide-Type AMPA Receptor Modulators Form Two Subfamilies with Distinct Modes of Action

Arai

Xia

Rogers

et al. 2002

J Pharmacol Exp Ther

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CX516 (BDP-12) and CX546, two first-generation benzamidetype AMPA receptor modulators, were compared with regard to their influence on AMPA receptor-mediated currents, autaptic responses in cultured hippocampal neurons, hippocampal excitatory postsynaptic currents, synaptic field potentials, and agonist binding. The two drugs exhibited comparable potencies in most tests but differed in their efficacy and in their relative impact on various response parameters. CX546 greatly prolonged the duration of synaptic responses, and it slowed 10-fold the deactivation of excised-patch currents following 1-ms pulses of glutamate. The effects of CX516 on those measures were, by comparison, small; however, the drug was equally or more efficacious than CX546 in increasing the amplitude of synaptic responses. This double dissociation suggests that amplitude and duration of synaptic responses are governed by different aspects of receptor kinetics, which are differentially modified by the two drugs. These effects can be reproduced in receptor simulations if one assumes that CX516 preferentially accelerates channel opening while CX546 slows channel closing. In binding tests, CX546 caused an approximately 2-fold increase in the affinity for radiolabeled agonists, whereas CX516 was ineffective. More importantly, even millimolar concentrations of CX516 did not influence the doseresponse relation for CX546, suggesting the possibility that they bind to different sites. Taken together, the evidence suggests that benzamide modulators from the Ampakine family form two subgroups with different modes and sites of action. Of these, CX516-type drugs may have the greater therapeutic utility because of their limited efficacy in prolonging synaptic responses and in attenuating receptor desensitization.AMPA receptor pharmacology has grown enormously during the last 10 years with the discovery of compounds that allosterically modulate these receptors. Two structurally distinct types of such compounds were initially found in short succession, namely, aniracetam (Ito et al., 1990) and the benzothiadiazides diazoxide and cyclothiazide (Yamada and Rothman, 1992;Yamada and Tang, 1993). Although both subtypes generally potentiate AMPA receptor responses, the nature of their interaction with the AMPA receptor was found to differ in many respects. Thus, aniracetam and cyclothiazide were differentially sensitive to amino acid modifications in the receptor, and they had distinct preference patterns for receptor subunits (Johansen et al., 1995;Partin et al., 1996). Such differences are likely to extend to structurally related compounds, in particular to a family of benzamide compounds called Ampakines, which were developed using aniracetam as the lead compound (Arai et al., 1994(Arai et al., , 1996a(Arai et al., ,b, 2000 Staubli et al., 1994a,b). Indeed, Ampakine modulators and cyclothiazide were shown to differ substantially in their effect on AMPA receptor-mediated responses (Arai et al., 1996a; Arai and Lynch, 1998a,b). In excisedpatch studies, ...

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Enantioselective synthesis of a pyrrolo-benzothiadiazine derivative S 18986, a new AMPA receptor positive modulator

Cited by 41 publications

References 20 publications

Effects of 5′-Alkyl-Benzothiadiazides on (R,S)-α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid (AMPA) Receptor Biophysics and Synaptic Responses

Effects of 5′-Alkyl-Benzothiadiazides on (R,S)-α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid (AMPA) Receptor Biophysics and Synaptic Responses

Glutamate Receptor Ion Channels: Structure, Regulation, and Function

Benzamide-Type AMPA Receptor Modulators Form Two Subfamilies with Distinct Modes of Action

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