LY341495 is a nanomolar potent and selective antagonist of group II metabotropic glutamate receptors

Abstract

The in vitro pharmacology of a structurally novel compound, LY341495, was investigated at human recombinant metabotropic glutamate (mGlu) receptor subtypes expressed in non-neuronal (RGT, rat glutamate transporter) cells. LY341495 was a nanomolar potent antagonist of 1 S,3 R-1-aminocyclopentane-1,3-dicarboxylic acid (ACPD)-induced inhibition of forskolin-stimulated cAMP formation at mGlu2 and mGlu3 receptors (respective IC 50s of 0.021 and 0.014 μM). At group I mGlu receptor expressing cells, LY341495 was micromolar potent in antagonizing quisqualate-induced phosphoinositide (PI) hydrolysis, with IC 50 values of 7.8 and 8.2 μM for mGlu1a and mGlu5a receptors, respectively. Among the human group III mGlu receptors, the most potent inhibition of l-2-amino-4-phosphonobutyric acid ( l-AP4) responses was seen for LY341495 at mGlu8, with an IC 50 of 0.17 μM. LY341495 was less potent at mGlu7 (IC 50=0.99 μM) and least potent at mGlu4 (IC 50=22 μM). Binding studies in rat brain membranes also demonstrated nanomolar potent group II mGlu receptor affinity for LY341495, with no appreciable displacement of ionotropic glutamate receptor ligand binding. Thus, LY341495 has a unique range of selectivity across the mGlu receptor subtypes with a potency order of mGlu3≥mGlu2>mGlu8>mGlu7⪢mGlu1a=mGlu5a>mGlu4. In particular, LY341495 is the most potent antagonist yet reported at mGlu2, 3 and 8 receptors. Thus, it represents a novel pharmacological agent for elucidating the function of mGlu receptors in experimental systems.