Pharmacological Characterization of cGMP Regulation by the Biarylpropylsulfonamide Class of Positive, Allosteric Modulators of α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid Receptors

  title={Pharmacological Characterization of cGMP Regulation by the Biarylpropylsulfonamide Class of Positive, Allosteric Modulators of $\alpha$-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid Receptors},
  author={John W. Ryder and Julie F. Falcone and Jason R. Manro and Kjell A. Svensson and Kalpana Mahesh Merchant},
  journal={Journal of Pharmacology and Experimental Therapeutics},
  pages={293 - 298}
The biarylpropylsulfonamide class of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) potentiators represented by N-2-(4-(4-cyanophenol)phenol)propyl-2-propanesulfonamide (LY404187) and (R)-4′-[1-fluoro-1-methyl-2-(propane-2-sulfonylamino)-ethyl]-biphenyl-4-carboxylic acid methylamide (LY503430) are positive, allosteric AMPA receptor activators, which enhance AMPA receptor-mediated neurotransmission by reducing desensitization of the ion channel. Although these compounds have… 

Figures from this paper

Discovery and characterization of a novel dihydroisoxazole class of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor potentiators.

The dihydroisoxazole (DHI) series of AMPAR potentiators described herein originated from the identification of 7 by a high-throughput functional activity screen using mouse embryonic stem (mES) cell-derived neuronal precursors and lead series optimization provided 16a, a functionally potent compound lacking the potentially bioactivatable aniline within 8a, but retaining desirable in vitro ADME properties.

The discovery and characterization of the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor potentiator N-{(3S,4S)-4-[4-(5-cyano-2-thienyl)phenoxy]tetrahydrofuran-3-yl}propane-2-sulfonamide (PF-04958242).

A unique tetrahydrofuran ether class of highly potent α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor potentiators has been identified using rational and structure-based drug design and suggests an adequate therapeutic index for clinical studies exploring its ability to attenuate cognitive deficits in patients with schizophrenia.

Positive Allosteric Modulation of AMPA Receptors from Efficacy to Toxicity: The Interspecies Exposure-Response Continuum of the Novel Potentiator PF-4778574

The resulting empirically derived exposure-response continuum for PF-4778574 defines a single-dose-based TI of 8- to 16-fold for self-limiting tremor, a readily monitorable clinical adverse event.

Functional Antagonism of Sphingosine-1-Phosphate Receptor 1 Prevents Harmaline-Induced Ultrastructural Alterations and Caspase-3 Mediated Apoptosis

The results suggest that FTY720 has potential efficacy for prevention of ET neurodegeneration and astrocytosis induced by harmaline in male rats.

Preclinical findings predicting efficacy and side‐effect profile of LY2940094, an antagonist of nociceptin receptors

Nociceptin/Orphanin FQ (N/OFQ) is a 17 amino acid peptide whose receptor is designated ORL1 or nociceptin receptor (NOP). We utilized a potent, selective, and orally bioavailable antagonist with

Selective inhibition of phosphodiesterase 5 enhances glutamatergic synaptic plasticity and memory in mice

It is suggested that moderate PDE5 inhibition enhances memory by increasing synaptic plasticity and transmission in the hippocampus, as well as enhancing cellular function, in healthy mice.

AMPA Receptor Positive Allosteric Modulators: Potential for the Treatment of Neuropsychiatric and Neurological Disorders.

This article reviews literature published in this area in the last 6 years, focusing on the new core templates, some derived from high-throughput screens, with an emphasis on structure-activity relationships, drug metabolism and pharmacokinetics properties, and pharmacological profiles of these series.

AMPA Receptors Regulate Exocytosis and Insulin Release in Pancreatic β Cells

A novel mechanism by which AMPARs participate in insulin release is uncovered by demonstrating that GluR2‐containing α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid receptors (AMPARs) were expressed in mouse β cells.



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

It is proposed that AMPA receptor potentiators offer the potential of a new disease modifying therapy for Parkinson's disease.

AMPA receptors: molecular and functional diversity.

Therapeutic potential of positive AMPA modulators and their relationship to AMPA receptor subunits. A review of preclinical data

  • M. Black
  • Biology, Psychology
  • 2004
Preclinical work on positive AMPA modulators is reviewed to suggest that positive modulation of AMPA may offer numerous therapeutic avenues for central nervous system drug discovery.

AMPA receptor potentiators for the treatment of CNS disorders.

Data indicate that these molecules modulate glutamatergic transmission, enhance synaptic transmission, long-term potentiation (LTP) and increase neurotrophin expression, and offer an exciting new class of drugs with potential for treating cognitive impairment associated with Alzheimer's disease and schizophrenia.

Amyloid-β Peptide Inhibits Activation of the Nitric Oxide/cGMP/cAMP-Responsive Element-Binding Protein Pathway during Hippocampal Synaptic Plasticity

Amyloid-β (Aβ), a peptide thought to play a crucial role in Alzheimer's disease (AD), has many targets that, in turn, activate different second-messenger cascades. Interestingly, Aβ has been found to

N-methyl-D-aspartic acid (NMDA) and non-NMDA receptors regulating hippocampal norepinephrine release. II. Evidence for functional cooperation and for coexistence on the same axon terminal.

The possible interactions between activation of N-methyl-D-aspartic acid (NMDA) receptors and non-NMDA receptors regulating the release of [3H]norepinephrine [( 3H]NE) have been investigated in

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

The evidence suggests that benzamide modulators from the Ampakine family form two subgroups with different modes and sites of action, and CX516-type drugs may have the greater therapeutic utility because of their limited efficacy in prolonging synaptic responses and in attenuating receptor desensitization.

In vivo studies of the cerebral glutamate receptor/NO/cGMP pathway