In Vitro Pharmacological and Rat Pharmacokinetic Characterization of LY3020371, a Potent and Selective mGlu2/3 Receptor Antagonist (original) (raw)

Neuropharmacology, 2015

Abstract

Small molecule modulators of glutamate neurotransmission continue to be of interest as therapeutic agents for the treatment of conditions for which aberrant glutamate signaling has been implicated. Metabotropic glutamate 2/3 (mGlu2/3) receptors have been of considerable interest in the field owing to their role in modulating glutamate transmission via presynaptic, postsynaptic and glial mechanisms. As part of our ongoing efforts to identify novel ligands for these receptors, we have discovered (1S,2R,3S,4S,5R,6R)-2-amino-3-[(3,4-difluorophenyl)sulfanylmethyl]-4-hydroxy-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid; (LY3020371), a potent and selective orthosteric mGlu2/3 receptor antagonist. In this account, we characterize the effects of LY3020371 and its HCl salt in membranes and cells expressing human recombinant mGlu receptor subtypes as well as in native rodent and human brain tissue preparations, providing important clone-to-native tissue translational information for this molecul...

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