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

• Published in: Bioorganic & medicinal chemistry letters Vol. 29; no. 2; pp. 297 - 301
• Main Authors: Hao, Junliang, Chen, Qi
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 15.01.2019
• Subjects: Conformation; Group selectivity; mGlu receptor; Scaffold; X-ray crystal structures; X-ray crystal structures; Group selectivity; Scaffold; mGlu receptor; Conformation
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2018.11.033

[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).