Design of antagonists for NMDA and AMPA receptors

Bolshakov, Konstantin V.; Kim, K.H.; Potapjeva, N. N.; Гмиро, В. Е.; Tikhonov, Denis B.; Usherwood, P.N.R.; Mellor, Ian R.; Lg, Magazanik

doi:10.1016/j.neuropharm.2005.02.007

Cited by 53 publications

(41 citation statements)

References 60 publications

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“…Thus, these channel blockers have been useful pharmacological tools to probe the subunit composition of AMPA receptors (Laezza et al, 1999;Liu and Cull-Candy, 2000;Plant et al, 2006), although many also show actions at kainate receptors. The amino groups of these compounds interact with residues that reside deeper in the pore than the QRN site, including the main-chain oxygen atom from the QRN ϩ 2 site (Tikhonov et al, 2002), and at least two amino groups are required for potent antagonism at AMPA receptors (Bolshakov et al, 2005). Some compounds (e.g., phenylcyclohexyl derivative IEM-1925) can permeate the channel, allowing closed channels to escape from block (Tikhonova et al, 2008).…”

Section: F Uncompetitive Antagonistsmentioning

confidence: 99%

“…It is noteworthy that pentamidine and 9-tetrahydroaminoacridine also inhibit currents of the mutant Lurcher GluD2 receptors (Williams et al, 2003). The structureactivity relationship underlying the trapping nature of blockers is unrelated to lipophilicity, and thus blockers are not capable of escaping through the membrane (Mealing et al, 2001;Bolshakov et al, 2005). Partially trapping blockers, such as memantine and amantadine, bind after channel opening.…”

Section: F Uncompetitive Antagonistsmentioning

confidence: 99%

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Glutamate Receptor Ion Channels: Structure, Regulation, and Function

et al. 2010

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Section: F Uncompetitive Antagonistsmentioning

confidence: 99%

Section: F Uncompetitive Antagonistsmentioning

confidence: 99%

Glutamate Receptor Ion Channels: Structure, Regulation, and Function

et al. 2010

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“…Целью настоящей работы было исследовать под-крепляющие свойства новых антагонистов NMDA-ре-цепторов ИЭМ-1921, ИЭМ-1791, ИЭМ-2181 и ан-тагониста АМРА-рецепторов ИЭМ-1460 [1,2,12], синтезированных в отделе нейрофармакологии им. С.В.…”

Section: обзоры по клинической фармакологии и лекарственной терапииunclassified

“…С.В. Аничкова [1,2,12]. В качестве соединений сравнения ис-пользовали фенциклидин [1-(1- [7]аннулен} (Sigma, США).…”

Section: методы исследованияunclassified

“…Таким образом, в настоящей работе мы иссле-довали антагонисты глутаматных NMDA-и AMPA-рецепторов в качестве потенциальных перспектив-ных средств для коррекции зависимости [12,13]. Были выбраны четыре соединения разной струк-туры с доказанным антагонистическим влияни-ем на NMDA-рецепторы (ИЭМ-1921, ИЭМ-1791, ИЭМ-2181) и АМРА-рецепторы (ИЭМ-1460) [7,18], синтезированные в отделе нейрофармакологии им.…”

Section: обсуждение полученных результатовunclassified

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Study of reinforcing properties of new antagonists of glutamate receptors

Potapkin

Лебедев

Гмиро

et al. 2017

Rev Clin Pharm Drug Ther

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Reinforcing properties of antagonists of NMDA receptors IEM-1921, IEM-1791, IEM-2181 and the antagonist of AMPA receptors IEM 1460 were investigated. Substances have been synthesized in S.V. Anichkov Dept. of Neuropharmacology Institute of Experimental Medicine. Electrodes were implanted into the lateral hypothalamus for brain stimulation reward. Rats were trained to press a pedal in Skinner box for receiving electric stimulation of the brain. IEM-1921 in doses of 1, 3 and 10 mg/kg enhanced number of pedal pressing and reduced self-stimulation thresholds more than phencyclidine (in doses 1, 3, 10 mg/kg) and MK-801 (in dose 1 and 3 mg/kg). IEM-1460 in doses of 1, 3 and 5 mg/kg reduced the frequency of hypothalamic self-stimulation and enhanced it thresholds. Also we investigated the conditional reinforcing properties of antagonists of glutamate receptors in conditional place preference test (CPP). The antagonist of NMDA receptors IEM 1921 did not cause CPP. The antagonist of AMPA receptors IEM 1460 caused CPP in dose of 3 mg/kg. IEM 1791 didn’t cause CPP. At the same time IEM 2181, the IEM 1791 water-soluble salt, caused CPP. Thus, the antagonist of NMDA of receptors of IEM-1921 increases the reinforcing properties of self-stimulation in rats more than phencyclidine and MK-801.This substance can be used as means analyzer for studying of the reinforcing properties of drugs. Antagonist of NMDA receptors IEM 2181cause CPP and has the conditional reinforcing properties. It is interesting that the antagonists of AMPA receptors IEM 1460 partially cause CPP, but reduced the reinforcing properties of self-stimulation.

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Design, Synthesis, and Pharmacological Characterization of Polyamine Toxin Derivatives: Potent Ligands for the Pore‐Forming Region of AMPA Receptors

et al. 2006

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Polyamine toxins, such as philanthotoxins, are low-molecular-weight compounds isolated from spiders and wasps, which modulate ligand-gated ion channels in the nervous system. Philanthotoxins bind to the pore-forming region of AMPA receptors, a subtype of glutamate receptors which are important for memory formation and are involved in neurodegenerative diseases. Previous studies have demonstrated that modification of the polyamine moiety of philanthotoxins can lead to very potent and highly selective ligands for the AMPA receptor, as exemplified with philanthotoxin-56. Much less attention has been paid to the importance of the aromatic head group of philanthotoxins, but herein we demonstrate that modification of this moiety leads to a significant improvement in potency relative to philanthotoxin-56 at cloned AMPA receptors. Interestingly, the incorporation of an adamantane moiety is particularly favorable, and the most potent compound has a Ki value of 2 nM, making it the most potent uncompetitive antagonist of AMPA receptors described to date. Such compounds are potentially useful as neuroprotective agents.

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Design of antagonists for NMDA and AMPA receptors

Cited by 53 publications

References 60 publications

Glutamate Receptor Ion Channels: Structure, Regulation, and Function

Glutamate Receptor Ion Channels: Structure, Regulation, and Function

Study of reinforcing properties of new antagonists of glutamate receptors

Design, Synthesis, and Pharmacological Characterization of Polyamine Toxin Derivatives: Potent Ligands for the Pore‐Forming Region of AMPA Receptors

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