On the origin of the 2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylate scaffold’s unique group II selectivity for the mGlu receptors

[Display omitted] •The conformation hypothesis for LY354740 and its analogs was reexamined.•A new steric hindrance hypothesis to account for their selectivity was proposed.•This was supported by the crystal structures of the mGlu ATD proteins. Analogs based on the 2-aminobicyclo[3.1.0]hexane-2,6-dic...

Ausführliche Beschreibung

Gespeichert in:
Bibliographische Detailangaben
Veröffentlicht in:Bioorganic & medicinal chemistry letters 2019-01, Vol.29 (2), p.297-301
Hauptverfasser: Hao, Junliang, Chen, Qi
Format: Artikel
Sprache:eng
Schlagworte:
Online-Zugang:Volltext
Tags: Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
Beschreibung
Zusammenfassung:[Display omitted] •The conformation hypothesis for LY354740 and its analogs was reexamined.•A new steric hindrance hypothesis to account for their selectivity was proposed.•This was supported by the crystal structures of the mGlu ATD proteins. Analogs based on the 2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylate scaffold showed high potency and selectivity as both group II mGlu receptors orthosteric agonists and antagonists. This scaffold was initially designed to mimic the fully extended glutamate backbone conformation that was hypothesized to be the active conformation for the group II mGlu receptors. With the availability of crystal structures of l-Glu-bound amino terminal domain proteins from multiple mGlu receptor subtypes spanning all three subgroups, a new steric hindrance hypothesis was proposed to account for the scaffold’s unique group II selectivity that explores the subtle distance differences between the α-carbon of l-Glu and the center of the tyrosine phenyl ring from the bottom lobe (e.g. Y216 of mGlu2).
ISSN:0960-894X
1464-3405
DOI:10.1016/j.bmcl.2018.11.033