AMPA Receptor-Positive Allosteric Modulators for the Treatment of Schizophrenia: An Overview of Recent Patent Applications

Ward, Simon E.; Pennicott, Lewis E.; Beswick, Paul J.

doi:10.4155/fmc.15.4

Cited by 28 publications

(16 citation statements)

References 62 publications

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“…Furthermore, polymorphisms in GRIA1 have been associated with schizophrenia and its clinical symptoms in different populations [66, 67]. Moreover, positive allosteric modulators of the AMPA receptor have become of increasingly high interest as potential new treatments for schizophrenia [68]. Based on these data, the increased expression we detected in the blood could likewise represent a possible compensatory response to glutamate transporter hypofunction in subjects with the hemi-deletion.…”

Section: Discussionmentioning

confidence: 95%

Characterization of a Novel Mutation in SLC1A1 Associated with Schizophrenia

Afshari¹,

Myles-Worsley

Cohen

et al. 2015

Complex Psychiatry

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We have recently described a hemi-deletion on chromosome 9p24.2 at the SLC1A1 gene locus and its co-segregation with schizophrenia in an extended Palauan pedigree. This finding represents a point of convergence for several pathophysiological models of schizophrenia. The present report sought to characterize the biological consequences of this hemi-deletion. Dual luciferase assays demonstrated that the partially deleted allele (lacking exon 1 and the native promoter) can drive expression of a 5′-truncated SLC1A1 using sequence upstream of exon 2 as a surrogate promoter. However, confocal microscopy and electrophysiological recordings demonstrate that the 5′-truncated SLC1A1 lacks normal membrane localization and glutamate transport ability. To identify downstream consequences of the hemi-deletion, we first used a themed qRT-PCR array to compare expression of 84 GABA and glutamate genes in RNA from peripheral blood leukocytes in deletion carriers (n = 11) versus noncarriers (n = 8) as well as deletion carriers with psychosis (n = 5) versus those without (n = 3). Then, targeted RNA-Seq (TREx) was used to quantify expression of 375 genes associated with neuropsychiatric disorders in HEK293 cells subjected to either knockdown of SLC1A1 or overexpression of full-length or 5′-truncated SLC1A1. Expression changes of several genes strongly implicated in schizophrenia pathophysiology were detected (e.g. SLC1A2, SLC1A3, SLC1A6, SLC7A11, GRIN2A, GRIA1 and DLX1).

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Section: Discussionmentioning

confidence: 95%

Characterization of a Novel Mutation in SLC1A1 Associated with Schizophrenia

Afshari¹,

Myles-Worsley

Cohen

et al. 2015

Complex Psychiatry

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“…Ligands with selectivea ffinity for theser eceptors have therapeutic potential for www.chemmedchem.org 2017 Wiley-VCH Verlag GmbH &Co. KGaA, Weinheim treating various neurological and mental disorders.I onotropic and metabotropic glutamate GABA and AMPAr eceptors (ligand-gated ion channels) are important for neurotransmission. [105,113] Effective agonists for some GABA receptors( 38;F igure 13) have eventually been developed. [111,112] Schizophrenia has been associated with such dysfunctions of synaptic transmission.…”

Section: Psychoactive Drugs (Psychotropics)mentioning

confidence: 99%

“…As eries of a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) modulators have been evaluated at the lead generation (hit-to-lead) stage, [104] and patent applications of such modulators for schizophrenia treatment have been reviewed. [105] Over the years,s elective neuronal nAChRa gonists have been developed for schizophrenia, attention deficit/hyperactivity disorder,and depression. [106,107] The long-known benzisoxazole zonisamide (33)a nd some aliphatic 34 or alicyclic 35 amine-substituted isoxazoles ( Figure 11)h ave been reported to have anticonvulsant activity and are used as anti-epileptics.…”

Section: Psychoactive Drugs (Psychotropics)mentioning

confidence: 99%

“…[111,112] Schizophrenia has been associated with such dysfunctions of synaptic transmission. [105,113] Effective agonists for some GABA receptors( 38;F igure 13) have eventually been developed. [114] In addition, GABA agonists 39 (Figure 13), of good affinity,b earing an alkyl or ab enzyl arm at the C4 position of an isoxazole ring, have also been developed.…”

Section: Psychoactive Drugs (Psychotropics)mentioning

confidence: 99%

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The Isoxazole Ring and Its N‐Oxide: A Privileged Core Structure in Neuropsychiatric Therapeutics

et al. 2017

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Mental disorders are neuropsychiatric conditions that are marked by unusual or irregular thinking, feelings, or behavior, and lead to distress and/or impaired functions. Major psychiatric conditions are depression, anxiety, and psychoses of various types. Their etiopathogeneses, of a primary or secondary origin, are associated with genetic and environmental factors. They are commonly treated with psychoactive drugs (also known as psychotropics), which target serotonin, dopamine, norepinephrine, glutamate, and nuclear receptors (NRs), including retinoic acid receptor-related orphan receptors (RORs) and other receptors in the central nervous system (CNS). Herein we present a diverse array of isoxazole derivatives, among which are some prominent marketed drugs. Some of the derivatives and forms, including N-oxides, are under either (pre)clinical evaluation or patent protection as new generation of psychotropics, and a few have effective blood-brain barrier (BBB) permeability. Various drug-like isoxazol(in)es and their structural features and efficiency, modified through scaffold hopping, are described and discussed in the context of treating neuropsychiatric conditions.

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“…Over time the modulators developed have become increasingly more potent for the AM-PAR, with the original benzamides being weaker than the phenethylsulfonamides. [78] As highlighted in our 2015 review of the AMPAR patent literature, [81] a number of novel chemotypes have recently been discovered, some of which are suggested to have a different mode of action and potentially a different clinical profile. This article will concentrate on new developments reported in the scientific literature over the last six years and not fully covered by previous reviews.…”

Section: Chemotypes Of Ampar Positive Allosteric Modulatorsmentioning

confidence: 99%

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

Reuillon

Ward²,

Beswick³

2016

CTMC

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The neurotransmitter glutamate and its receptors have long been of interest to scientists involved in pharmaceutical research since dysfunction of the glutamatergic signalling pathway has been associated with the pathophysiology of several psychiatric and neurological disorders. The research on AMPAR positive allosteric modulators offers opportunities to modulate fast excitatory synaptic transmission and identify new potential therapeutic agents for a range of neurodiseases. The field of AMPAR modulators continues to be a dynamic area of drug discovery with a pronounced diversification of the chemotypes explored in recent years. 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.

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AMPA Receptor-Positive Allosteric Modulators for the Treatment of Schizophrenia: An Overview of Recent Patent Applications

Cited by 28 publications

References 62 publications

Characterization of a Novel Mutation in <b><i>SLC1A1 </i></b>Associated with Schizophrenia

Characterization of a Novel Mutation in <b><i>SLC1A1 </i></b>Associated with Schizophrenia

The Isoxazole Ring and Its N‐Oxide: A Privileged Core Structure in Neuropsychiatric Therapeutics

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

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