title: 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.
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 noncompetitive 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 BDZ-11-6, 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.
authors.affiliation: †Department of Chemistry and Center for Neuroscience Research, University at Albany, Albany, New York 12222, United States.
authors.forename: Congzhou
authors.initials: C
authors.lastname: Wang
authors.affiliation: †Department of Chemistry and Center for Neuroscience Research, University at Albany, Albany, New York 12222, United States.
authors.forename: Andrew
authors.initials: A
authors.lastname: Wu
authors.affiliation: †Department of Chemistry and Center for Neuroscience Research, University at Albany, Albany, New York 12222, United States.
authors.forename: Yu-Chuan
authors.initials: YC
authors.lastname: Shen
authors.affiliation: ‡Department of Drug Sciences and Products for Health, University of Messina, Viale Annunziata, 98168 Messina, Italy.
authors.forename: Roberta
authors.initials: R
authors.lastname: Ettari
authors.affiliation: §Department of Chemical Sciences, University of Messina, Via F. Stagno D'Alcontres 31, 98166 Messina, Italy.
authors.forename: Silvana
authors.initials: S
authors.lastname: Grasso
authors.affiliation: †Department of Chemistry and Center for Neuroscience Research, University at Albany, Albany, New York 12222, United States.
authors.forename: Li
authors.initials: L
authors.lastname: Niu
mesh_terms: D001569:Benzodiazepines / Q000737:chemistry* / Q000494:pharmacology*; D018691:Excitatory Amino Acid Antagonists / Q000737:chemistry* / Q000494:pharmacology*; D057809:HEK293 Cells; D006801:Humans; D007700:Kinetics; D007834:Lasers; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D018408:Patch-Clamp Techniques; D010782:Photolysis; D018091:Receptors, AMPA / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D018691:Excitatory Amino Acid Antagonists; D018091:Receptors, AMPA; D001569:Benzodiazepines
keywords: 2,3-benzodiazepine; AMPA receptors; Glutamate receptors; antagonist; structure−activity relationship