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.
Department of Pharmacology, Tokyo Metropolitan Institute of Medical Science, Japan.
M
M
Ishida
T
T
Saitoh
K
K
Tsuji
Y
Y
Nakamura
K
K
Kataoka
H
H
Shinozaki
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