2,3-Benzodiazepines are a well-known group of compounds for their potential antagonism against AMPA receptors. It has been previously reported that the inhibitory effect of 2,3- benzodiazepine derivatives with a 7,8-ethylenedioxy moiety can be enhanced by simply adding a chlorine atom at position 3 of the 4-aminophenyl ring. Here we report that adding a methyl group at position 3 on the 4-aminophenyl ring, termed as BDZ-11-7, can similarly enhance the inhibitory activity, as compared with the unsubstituted one or BDZ-11-2. Our kinetic studies have shown that BDZ-11-7 is a non competitive antagonist of GluA2Q homomeric receptors and prefers to inhibit the closed-channel state. However, adding another methyl group at position 5 on the 4-aminophenyl ring, termed as BDZ11-6, fails to yield extra inhibition on GluA2Q receptors. Instead, BDZ-11-6 exhibits a diminished inhibition of GluA2Q. Site interaction test indicates the two compounds, BDZ-11-6 and BDZ-11-7, bind to the same site on GluA2Q, which is also the binding site for their prototype, BDZ-11-2. Based on the results from this and our earlier studies, we propose that the binding site that accommodates the 4-aminophenyl ring must contain two interactive points, with one preferring polar groups like chlorine and the other preferring nonpolar groups such as a methyl group. Either adding a chlorine or a methyl group may enhance the inhibitory activity of 2,3-benzodiazepine derivatives with a 7,8-ethylenedioxy moiety. Adding any two of the same group on positions 3 and 5 of the 4-aminophenyl ring, however, significantly reduces the interaction between these 2,3-benzodiazepines and their binding site, because one group is always repelled by one interactive point. We predict therefore that adding a chlorine atom at position 3 and a methyl group at position 5 of the 4-aminophenyl ring of 2,3- benzodiazepine derivatives with a 7,8-ethylenedioxy moiety may produce a new compound that is more potent.

Mechanism and Site of Inhibition of AMPA Receptors: Substitution of One and Two Methyl groups at the 4-Aminophenyl Ring of 2,3-Benzodiazepine and Implications in the “E” Site

ETTARI, Roberta;GRASSO, Silvana
Penultimo
;
2015-01-01

Abstract

2,3-Benzodiazepines are a well-known group of compounds for their potential antagonism against AMPA receptors. It has been previously reported that the inhibitory effect of 2,3- benzodiazepine derivatives with a 7,8-ethylenedioxy moiety can be enhanced by simply adding a chlorine atom at position 3 of the 4-aminophenyl ring. Here we report that adding a methyl group at position 3 on the 4-aminophenyl ring, termed as BDZ-11-7, can similarly enhance the inhibitory activity, as compared with the unsubstituted one or BDZ-11-2. Our kinetic studies have shown that BDZ-11-7 is a non competitive antagonist of GluA2Q homomeric receptors and prefers to inhibit the closed-channel state. However, adding another methyl group at position 5 on the 4-aminophenyl ring, termed as BDZ11-6, fails to yield extra inhibition on GluA2Q receptors. Instead, BDZ-11-6 exhibits a diminished inhibition of GluA2Q. Site interaction test indicates the two compounds, BDZ-11-6 and BDZ-11-7, bind to the same site on GluA2Q, which is also the binding site for their prototype, BDZ-11-2. Based on the results from this and our earlier studies, we propose that the binding site that accommodates the 4-aminophenyl ring must contain two interactive points, with one preferring polar groups like chlorine and the other preferring nonpolar groups such as a methyl group. Either adding a chlorine or a methyl group may enhance the inhibitory activity of 2,3-benzodiazepine derivatives with a 7,8-ethylenedioxy moiety. Adding any two of the same group on positions 3 and 5 of the 4-aminophenyl ring, however, significantly reduces the interaction between these 2,3-benzodiazepines and their binding site, because one group is always repelled by one interactive point. We predict therefore that adding a chlorine atom at position 3 and a methyl group at position 5 of the 4-aminophenyl ring of 2,3- benzodiazepine derivatives with a 7,8-ethylenedioxy moiety may produce a new compound that is more potent.
2015
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Descrizione: ACS Chemical Neuroscience, 2015, 6, 1371-1378
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11570/3062855
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