Biarylpropylsulfonamides as Novel, Potent Potentiators of 2-Amino-3- (5-methyl-3-hydroxyisoxazol-4-yl)- propanoic Acid (AMPA) Receptors

Ornstein, Paul L.; Zimmerman, Dennis M.; Mb, Arnold; Tj, Bleisch; Cantrell, Buddy E.; Simon, Richard L.; Zarrinmayeh, Hamideh; Baker,; Gates, Mary; Jp, Tizzano; Bleakman, David; Mandelzys, Allan; Kr, Jarvie; K, Ho; Deverill, Michelle; Rk, Kamboj

doi:10.1021/jm0002836

Cited by 70 publications

(46 citation statements)

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“…After the discovery that cyclothiazide and IDRA 21 could potentiate AMPA receptor activity, more potent and selective AMPA receptor potentiators have been discovered (Ornstein et al, 2000;Baumbarger et al, 2001b;Parsons et al, 2002). All of these compounds allosterically regulate AMPA receptor activity at least in part by suppressing the desensitization process of AMPA receptors.…”

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confidence: 99%

LY503430, a Novel α-Amino-3-hydroxy-5-methylisoxazole-4-propionic Acid Receptor Potentiator with Functional, Neuroprotective and Neurotrophic Effects in Rodent Models of Parkinson's Disease

Murray

Whalley²,

Robinson³

et al. 2003

J Pharmacol Exp Ther

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Glutamate is the major excitatory transmitter in the brain. Recent developments in the molecular biology and pharmacology of the ␣-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) subtype of glutamate receptors have led to the discovery of selective, potent, and systemically active AMPA receptor potentiators. These molecules enhance synaptic transmission and play important roles in plasticity and cognitive processes. In the present study, we first characterized a novel AMPA receptor potentiator, (R)-4Ј-[1-fluoro-1-methyl-2-(propane-2-sulfonylamino)-ethyl]-biphenyl-4-carboxylic acid methylamide (LY503430), on recombinant human GLU A1-4 and native preparations in vitro and then evaluated the potential neuroprotective effects of the molecule in rodent models of Parkinson's disease. Results indicated that submicromolar concentrations of LY503430 selectively enhanced glutamate-induced calcium influx into human embryonic kidney 293 cells transfected with human GLU A1 , GLU A2 , GLU A3 , or GLU A4 AMPA receptors. The molecule also potentiated AMPA-mediated responses in native cortical, hippocampal, and substantia nigra neurons. We also report here that LY503430 provided dose-dependent functional and histological protection in animal models of Parkinson's disease. The neurotoxicity after unilateral infusion of 6-hydroxydopamine into either the substantia nigra or the striatum of rats and that after systemic 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine in mice were reduced. Interestingly, LY503430 also had neurotrophic actions on functional and histological outcomes when treatment was delayed until well after (6 or 14 days) the lesion was established. LY503430 also produced some increase in brain-derived neurotrophic factor in the substantia nigra and a dose-dependent increases in growth associated protein-43 (GAP-43) expression in the striatum. Therefore, we propose that AMPA receptor potentiators offer the potential of a new disease modifying therapy for Parkinson's disease.Parkinson's disease (PD) is a movement disorder resulting from neurodegeneration of the basal ganglia, the most prominent pathological change in Parkinsonian brains being the loss of dopaminergic innervation from the substantia nigra (SN) to the caudate and putamen of the corpus striatum. There are several available therapies to treat the symptoms (i.e., replacement of dopamine), but none halt or even slow the progression of the disease (O'Neill and Siemers, 2002). The exact mechanism of Lewy body formation and subsequent nigral cell death and the role played by environmental and genetic factor remain to be elucidated. However, it is clear that agents that halt the progression or help repair the damage are urgently required (O'Neill and Siemers, 2002).

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confidence: 99%

LY503430, a Novel α-Amino-3-hydroxy-5-methylisoxazole-4-propionic Acid Receptor Potentiator with Functional, Neuroprotective and Neurotrophic Effects in Rodent Models of Parkinson's Disease

Murray

Whalley²,

Robinson³

et al. 2003

J Pharmacol Exp Ther

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100

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“…Sekiguchi et al 19 and Ornstein et al 39 recently described new potent AMPA receptor modulators (Fig. 1).…”

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confidence: 99%

5′-Alkyl-benzothiadiazides: A New Subgroup of AMPA Receptor Modulators with Improved Affinity

Phillips

Sonnenberg

Arai

et al. 2002

Bioorganic & Medicinal Chemistry

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“…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. It will be of interest to compare these compounds with the alkyl-BTDs in the paradigms used here, because they have not yet been fully characterized regarding their effects on the synaptic waveform, receptor kinetics, or agonist binding.…”

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confidence: 99%

“…Other compounds were subsequently discovered that "up-modulate" or "potentiate" AMPA receptor function in a similar manner, including diazoxide (Yamada and Rothman, 1992), cyclothiazide (Yamada and Tang, 1993), IDRA-21 (Bertolino et al, 1993), and PEPA (Sekiguchi et al, 1997). Using the structural leads given by these compounds, several laboratories have developed entire families of potent AMPA receptor modulators beginning with the ampakines (Arai et al, 1994(Arai et al, , 1996b(Arai et al, ,c, 2000Staubli et al, 1994a,b) and including the pyridothiadiazines (Pirotte et al, 1998) and the biarylpropylsulfonamides (Ornstein et al, 2000).…”

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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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Biarylpropylsulfonamides as Novel, Potent Potentiators of 2-Amino-3- (5-methyl-3-hydroxyisoxazol-4-yl)- propanoic Acid (AMPA) Receptors

Cited by 70 publications

References 11 publications

LY503430, a Novel α-Amino-3-hydroxy-5-methylisoxazole-4-propionic Acid Receptor Potentiator with Functional, Neuroprotective and Neurotrophic Effects in Rodent Models of Parkinson's Disease

LY503430, a Novel α-Amino-3-hydroxy-5-methylisoxazole-4-propionic Acid Receptor Potentiator with Functional, Neuroprotective and Neurotrophic Effects in Rodent Models of Parkinson's Disease

5′-Alkyl-benzothiadiazides: A New Subgroup of AMPA Receptor Modulators with Improved Affinity

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

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