Novel agonists for metabotropic glutamate receptors: trans- and cis-2-(2-carboxy-3-methoxymethylcyclopropyl)glycine (trans- 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 microM, 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 1 microM (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.
Ishida
M
M
Department of Pharmacology, Tokyo Metropolitan Institute of Medical Science, Japan.
Saitoh
T
T
Tsuji
K
K
Nakamura
Y
Y
Kataoka
K
K
Shinozaki
H
H
D000818:Animals; D000831:Animals, Newborn; D002478:Cells, Cultured; D005576:Colforsin / Q000037:antagonists & inhibitors / Q000494:pharmacology; D000242:Cyclic AMP / Q000096:biosynthesis; D004594:Electrophysiology; D018690:Excitatory Amino Acid Agonists / Q000138:chemical synthesis* / Q000494:pharmacology*; D005998:Glycine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D066298:In Vitro Techniques; D008297:Male; D016318:Quisqualic Acid / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D018094:Receptors, Metabotropic Glutamate / Q000819:agonists* / Q000378:metabolism; D012018:Reflex / Q000187:drug effects; D013116:Spinal Cord / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D013569:Synapses / Q000187:drug effects
D018690:Excitatory Amino Acid Agonists; D018094:Receptors, Metabotropic Glutamate; C090522:2-(2-carboxy-3-methoxymethylcyclopropyl)glycine; D005576:Colforsin; D016318:Quisqualic Acid; D000242:Cyclic AMP; D005998:Glycine