Comparisons of the influenza virus A M2 channel binding affinities, anti-influenza virus potencies and NMDA antagonistic activities of 2-alkyl-2-aminoadamantanes and analogues.
Identifieur interne : 001270 ( Main/Exploration ); précédent : 001269; suivant : 001271Comparisons of the influenza virus A M2 channel binding affinities, anti-influenza virus potencies and NMDA antagonistic activities of 2-alkyl-2-aminoadamantanes and analogues.
Auteurs : Antonios Kolocouris [Grèce] ; Philip Spearpoint ; Stephen R. Martin ; Alan J. Hay ; Marta L Pez-Querol ; Francesc X. Sureda ; Elizaveta Padalko ; Johan Neyts ; Erik De ClercqSource :
- Bioorganic & medicinal chemistry letters [ 1464-3405 ] ; 2008.
Descripteurs français
- KwdFr :
- Adamantane (), Adamantane (analogues et dérivés), Adamantane (pharmacologie), Adamantane (synthèse chimique), Amantadine (pharmacologie), Antiviraux (), Antiviraux (pharmacologie), N-Méthyl-aspartate (antagonistes et inhibiteurs), Protéines de la matrice virale (), Relation structure-activité, Structure moléculaire, Virus de la grippe A ().
- MESH :
- analogues et dérivés : Adamantane.
- antagonistes et inhibiteurs : N-Méthyl-aspartate.
- pharmacologie : Adamantane, Amantadine, Antiviraux.
- synthèse chimique : Adamantane.
- Adamantane, Antiviraux, Protéines de la matrice virale, Relation structure-activité, Structure moléculaire, Virus de la grippe A.
English descriptors
- KwdEn :
- Adamantane (analogs & derivatives), Adamantane (chemical synthesis), Adamantane (chemistry), Adamantane (pharmacology), Amantadine (pharmacology), Antiviral Agents (chemistry), Antiviral Agents (pharmacology), Influenza A virus (drug effects), Molecular Structure, N-Methylaspartate (antagonists & inhibitors), Structure-Activity Relationship, Viral Matrix Proteins (drug effects).
- MESH :
- chemical , analogs & derivatives : Adamantane.
- chemical , antagonists & inhibitors : N-Methylaspartate.
- chemical , chemical synthesis : Adamantane.
- chemical , chemistry : Adamantane, Antiviral Agents.
- chemical , drug effects : Viral Matrix Proteins.
- chemical , pharmacology : Adamantane, Amantadine, Antiviral Agents.
- drug effects : Influenza A virus.
- Molecular Structure, Structure-Activity Relationship.
Abstract
The new 2-alkyl-2-aminoadamantanes and analogues 4-10 were designed and synthesized by simplification of the structure of the potent anti-influenza virus A spiranic aminoadamantane heterocycles 2 and 3. The aim of the present work was to examine the effects of bulky and extended lipophilic moieties attached to amantadine 1 on binding to the M2 channel and the resulting antiviral potency. The binding affinities of the compounds to the M2 protein of influenza virus A/chicken/Germany/27 (Weybridge strain; H7N7) were measured for the first time using an assay based on quenching of Trp-41 fluorescence by His-37 protonation, and their antiviral potencies were evaluated against the replication of influenza virus A H2N2 and H3N2 subtypes and influenza virus B in MDCK cells. Of the various 2-alkyl-2-aminoadamantanes, and analogues, spiro[piperidine-2,2'-adamantane] 3 had the strongest M2 binding and antiviral potency, which were similar those of amantadine 1. The relative binding affinities suggested that the rigid carbon framework provided by the pyrrolidine or piperidine rings results in a more favorable orientation inside the M2 channel pore as compared to large, freely rotating alkyl groups. The aminoadamantane derivatives exhibited similar NMDA antagonistic activity to amantadine 1. A striking finding was the antiviral activity of the adamantanols 4, and 6, which lack any NMDA antagonist activity.
DOI: 10.1016/j.bmcl.2008.10.003
PubMed: 18947998
Affiliations:
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Le document en format XML
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The aim of the present work was to examine the effects of bulky and extended lipophilic moieties attached to amantadine 1 on binding to the M2 channel and the resulting antiviral potency. The binding affinities of the compounds to the M2 protein of influenza virus A/chicken/Germany/27 (Weybridge strain; H7N7) were measured for the first time using an assay based on quenching of Trp-41 fluorescence by His-37 protonation, and their antiviral potencies were evaluated against the replication of influenza virus A H2N2 and H3N2 subtypes and influenza virus B in MDCK cells. Of the various 2-alkyl-2-aminoadamantanes, and analogues, spiro[piperidine-2,2'-adamantane] 3 had the strongest M2 binding and antiviral potency, which were similar those of amantadine 1. The relative binding affinities suggested that the rigid carbon framework provided by the pyrrolidine or piperidine rings results in a more favorable orientation inside the M2 channel pore as compared to large, freely rotating alkyl groups. The aminoadamantane derivatives exhibited similar NMDA antagonistic activity to amantadine 1. A striking finding was the antiviral activity of the adamantanols 4, and 6, which lack any NMDA antagonist activity.</div></front></TEI><affiliations><list><country><li>Grèce</li></country></list><tree><noCountry><name sortKey="De Clercq, Erik" sort="De Clercq, Erik" uniqKey="De Clercq E" first="Erik" last="De Clercq">Erik De Clercq</name><name sortKey="Hay, Alan J" sort="Hay, Alan J" uniqKey="Hay A" first="Alan J" last="Hay">Alan J. Hay</name><name sortKey="L Pez Querol, Marta" sort="L Pez Querol, Marta" uniqKey="L Pez Querol M" first="Marta" last="L Pez-Querol">Marta L Pez-Querol</name><name sortKey="Martin, Stephen R" sort="Martin, Stephen R" uniqKey="Martin S" first="Stephen R" last="Martin">Stephen R. Martin</name><name sortKey="Neyts, Johan" sort="Neyts, Johan" uniqKey="Neyts J" first="Johan" last="Neyts">Johan Neyts</name><name sortKey="Padalko, Elizaveta" sort="Padalko, Elizaveta" uniqKey="Padalko E" first="Elizaveta" last="Padalko">Elizaveta Padalko</name><name sortKey="Spearpoint, Philip" sort="Spearpoint, Philip" uniqKey="Spearpoint P" first="Philip" last="Spearpoint">Philip Spearpoint</name><name sortKey="Sureda, Francesc X" sort="Sureda, Francesc X" uniqKey="Sureda F" first="Francesc X" last="Sureda">Francesc X. Sureda</name></noCountry><country name="Grèce"><noRegion><name sortKey="Kolocouris, Antonios" sort="Kolocouris, Antonios" uniqKey="Kolocouris A" first="Antonios" last="Kolocouris">Antonios Kolocouris</name></noRegion></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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