LY354740 IS A POTENT AND HIGHLY SELECTIVE GROUP-II METABOTROPIC GLUTAMATE-RECEPTOR AGONIST IN CELLS EXPRESSING HUMAN GLUTAMATE RECEPTORS

The novel compound LY354740 is a conformationally constrained analog o f glutamate, which was designed for interaction at metabotropic glutam ate (mGlu) receptors. In this paper the selectivity of LY354740 for re combinant human mGlu receptor subtypes expressed in non-neuronal (RGT) cells is described. At human mGlu2 receptors, LY354740 produced >90% suppression of forskolin-stimulated cAMP formation with an EC(50) Of 5 .1 +/- 0.3 nM. LY354740 was six-fold less potent in activating human m Glu3 receptors (EC(50) = 24.3 +/- 0.5 nM). LY354740 inhibition of fors kolin-stimulated cAMP formation in human mGlu2 receptor-expressing cel ls was blocked by competitive mGlu receptor antagonists, including (+) -alpha-methyl-4-carboxyphenylglycine (MCPG) and LY307452 2-amino-4-(4, 4-diphenylbut-1-yl)-pentane-1,5-dioic acid). LY354740 had no agonist o r antagonist activities at cells expressing human mGlu4 or mGlu7 (grou p III mGlu receptors) (EC(50)5 > 100 000 nM). When tested at group I p hosphoinositide-coupled human mGlu receptors (mGlu1a and mGlu5a), LY35 4740 did not activate or inhibit mGlu receptor agonist-evoked phosphoi nositide hydrolysis at up to 100 000 nM. Electrophysiological experime nts also demonstrated that LY354740 also had no appreciable activity i n cells expressing human recombinant AMPA (GluR4) and kainate (GluR6) receptors. Thus, LY354740 is a highly potent, efficacious and selectiv e group II (mGlu2/3) receptor agonist, useful to explore the functions of these receptors in situ. (C) 1997 Elsevier Science Ltd.