POTENT, STEREOSELECTIVE, AND BRAIN REGION SELECTIVE MODULATION OF 2NDMESSENGERS IN THE RAT-BRAIN BY (-II METABOTROPIC GLUTAMATE-RECEPTOR AGONIST()LY354740, A NOVEL GROUP)

LY354740 is a highly potent and selective agonist for recombinant Grou p IT mGlu receptors (mGlu2 and mGlu3), which has anxiolytic and drug w ithdrawal alleviating properties when administered systemically in rat s and mice. The modulation of second messengers by LY354740 in rat bra in tissues was investigated to understand the cellular basis for the p harmacological and potential therapeutic actions of LY354740. LY354740 potently decreased forskolin-stimulated cAMP formation in slices of t he adult rat hippocampus (EC50=22+/-3 nM) in a stereoselective manner. LY354740 (at 1 mu M) greatly (>90%) suppressed forskolin-stimulated c AMP in the cerebral cortex, hippocampus, and striatum, while producing only partial suppression (about 50%) in midbrain regions and olfactor y bulb, and no significant cAMP alterations in the cerebellum and brai nstem regions. Inhibition of forskolin-stimulate cAMP formation was an tagonized by (+)-alpha-methyl-4-carboxyphenylglycine [(+)MCPG], a comp etitive mGlu receptor antagonist. LY354740 did not alter phosphoinosit ide hydrolysis in the rat hippocampus per se, but potentiated stimulat ion of phophoinositide hydrolysis by the Group I mGlu receptor selecti ve agonist 3,5-dihydroxyphenylglycine (DHPG) or stimulation of cAMP fo rmation by the adenosine receptor agonist 5'-N-ethylcarboxamideoadenos ine (NECA). These data indicate that LY354740 is a highly potent, effi cacious, and selective Group II mGlu receptor (mGlu 2/3) agonist in th e rat brain. The potent, stereoselective, and brain region selective a ctions of LY354740 on mGlu receptor linked second messenger systems li kely underlie the in vivo potency and stereoselectivity of this compou nd in animal models.