New 4-Functionalized Glutamate Analogues Are Selective Agonists at Metabotropic Glutamate Receptor Subtype 2 or Selective Agonists at Metabotropic Glutamate Receptor Group III

Abstract

The metabotropic glutamate (Glu) receptors (mGluRs) play key roles in modulating excitatory neurotransmission in the brain. In all, eight subtypes have been identified and divided into three groups, group I (mGlu1,5), group II (mGlu2,3), and group III (mGlu4,6-8). In this article, we present a L-2,4-syn-substituted Glu analogue, 1d, which displays selective agonist activity at mGlu2 over the remaining mGluR subtypes. A modeling study and redesign of the core scaffold led to the stereoselective synthesis of four new conformationally restricted Glu analogues, 2a-d. Most interestingly, 2a retained a selective agonist activity profile at mGlu2 (EC50 in the micromolar range), whereas 2c/2d were both selective agonists at group III, subtypes mGlu4,6,8. In general, 2d was 20-fold more potent than 2c and potently activated mGlu4,6,8 in the low-mid nanomolar range.

Dual optical control and mechanistic insights into photoswitchable group II and III metabotropic glutamate receptors

“…In contrast to LimGluR3, which shows very robust photoactivation with D-MAG-0 (∼70%), we show in this study that SNAP-mGluR3 is weakly agonized by BGAG (∼20%). This is consistent with pharmacological studies that have shown that many 4-functionalized glutamate compounds have a higher affinity for mGluR2 than mGluR3 (32). In addition, SNAP-mGluR3 has a more pronounced dependence on BGAG length than SNAP-mGluR2.…”

Acid‐Catalyzed Intramolecular Imination / Nucleophilic Trapping of 4‐Aminobutanal Derivatives: One‐Pot Access to 2‐(Pyrazolyl)pyrrolidines

“…The formation of compounds 9 is likely to proceed via Mannich‐type reaction of enolized pyrazolidin‐3‐one 7 . Notably, carboxylic acid derivatives, both cyclic and acyclic, usually require usage of either strong bases, or Lewis acid/base combination, to undergo the reaction with iminium ion. To the best of our knowledge, no such reactions in the presence of Bronsted acid were reported until now.…”

Computer-Aided Drug Design Approaches to Study Key Therapeutic Targets in Alzheimer’s Disease

“…The symptomatic and neuroprotective properties of group III mGluRs agonists are prevented in mGluR 4 knockout mice, which suggest that the modulation of mGluR 4 has the potential to exert antiparkinsonian activity in animal models. Overall, the pharmacological activation with mGluR 2 /mGluR 3 [175][176][177][178][179][180] and mGluR 4 [181][182][183][184][185][186] with agonists and positive allosteric modulators may offer an alternative approach for PD therapeutics.…”