NOVEL AGONISTS FOR METABOTROPIC GLUTAMATE RECEPTORS - TRANS-2-(2-CARBOXY-3-METHOXYMETHYLCYCLOPROPYL)GLYCINE AND CIS-2-(2-CARBOXY-3-METHOXYMETHYLCYCLOPROPYL)GLYCINE (TRANS-MCG-I AND CIS-MCG-I)

New derivatives of 2-(carboxycyclopropyl)glycine (CCG), (2S,1'S,2'R,3'S)- and (2S,1'S,2'R,3'R)-2-(2-carboxy-3-methoxymethylcyclopropyl)glycine (trans- and cis-MCG-I), effectively inhibited forskolin-stimulated cyclic AMP formation in a concentration dependent manner in cultured spinal neurones of rats. They effectively depressed monosynaptic excitation in the spinal reflex of newborn rats with IC50 values of 0.3 and 3 mu M, respectively, which was sensitive to (+)-MCPG. They did not cause any depolarization even when the concentration was increased up to 0.3 mM. However, after treatment with quisqualate, cis-MCG-I caused a depolarization of motoneurones in the newborn rat spinal cord in a concentration dependent manner with a threshold concentration of 3 mu M (quisqualate effect). The depolarizing activity developed after quisqualate treatment gradually decreased but lasted for more than 2 hr. The depolarization induced by cis-MCG-I seemed pharmacologically similar to that of phosphonate-containing analogues of glutamate such as L-AP4 or L-AP6 under the ''quisqualate effect''. These novel CCG derivatives would be expected to provide useful probes for elucidating the physiological function of mGluRs.