2022
DOI: 10.1016/j.mencom.2022.05.023
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Positive and negative AMPA receptor modulators based on tricyclic bispidine derivative: Minor structural change inverts the type of activity

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Cited by 8 publications
(7 citation statements)
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“…In agreement with both the X-ray and molecular modeling data [11,[18][19][20]22,23,[48][49][50][51] for other larger and dimeric ("Class 3" [48]) modulators, the modulator molecules are located in the symmetrical PAM binding site, occupying its central subpocket as well as one or both of the side subpockets (Figure S1). As an example, the binding mode of the most potent PAM molecule 3j is examined in detail in Figure 2.…”
Section: Molecular Modelingsupporting
confidence: 82%
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“…In agreement with both the X-ray and molecular modeling data [11,[18][19][20]22,23,[48][49][50][51] for other larger and dimeric ("Class 3" [48]) modulators, the modulator molecules are located in the symmetrical PAM binding site, occupying its central subpocket as well as one or both of the side subpockets (Figure S1). As an example, the binding mode of the most potent PAM molecule 3j is examined in detail in Figure 2.…”
Section: Molecular Modelingsupporting
confidence: 82%
“…There is a particular interest in the bivalent ligands of the AMPA receptor because of their unique ability to bind simultaneously by two parts of the molecule at a close distance from each other in the pocket located at the interface between two subunits of the receptor [11,18,19]. Recently we reported several novel series of dimeric AMPA receptor PAMs based on different scaffolds; for many of them, potencies in the nanomolar or picomolar concentration ranges were demonstrated in the patch clamp experiments [20][21][22][23]. Amazingly, in many cases substantial differences in activity are found even for very similar structures, e.g., one structure could be a potent PAM while another is a potent NAM [11].…”
Section: Introductionmentioning
confidence: 99%
“…The compounds’ binding in the PAM binding site, at the interface between the ligand binding domains, was stable over the entire course of the simulation (150 ns). In a similar way to the other larger dimeric modulators [ 27 , 28 , 37 , 38 ], the modulator molecules attained an unsymmetric “lateral” position, occupying one of the side subpockets as well as part of the central subpocket of the symmetrical PAM binding site ( Figure 3 A,B, Figure 4 A,B and Figure 5 A,B). The binding was primarily stabilized by steric fit and hydrophobic interactions ( Figure 3 B,C, Figure 4 B,C and Figure 5 B,C) and a number of hydrogen bonds for compound 1i .…”
Section: Resultsmentioning
confidence: 64%
“…This could explain the lack (or lower efficiency) of the positive modulator activity. On the other hand, similar to the tricyclic modulators [ 38 ], the negative modulator action of compound 1j could potentially be mediated by competing interactions with the NAM binding sites at the interface between the LBD and the transmembrane domain (TMD).…”
Section: Resultsmentioning
confidence: 99%
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