Potentiation by DL ‐ α ‐aminopimelate of the inhibitory action of a novel mGluR agonist (L‐F 2 CCG‐I) on monosynaptic excitation in the rat spinal cord

Neuropharmacological actions of all the possible stereoisomers of 3′,3′‐difluoro‐2‐(carboxycyclopropyl)glycine (3′,3′‐difluoro‐CCG) were compared with those of the corresponding 2‐(carboxycyclopropyl)glycine (CCG) isomers in the isolated spinal cord of newborn rats. (2 S ,1′ S ,2′ S )‐ and (2 S ,1′ R ,2′ S )‐2‐(2‐carboxy‐3,3‐difluorocyclopropyl)glycine ( L ‐F 2 CCG‐I and L ‐F 2 CCG‐IV) were the most potent in causing depolarization, their threshold concentrations being approximately 1 μ M . The depolarization evoked by L ‐F 2 CCG‐I (30 μ M ) was depressed by (+)‐α‐methyl‐4‐carboxyphenylglycine (MCPG, 1 m M ( n =4)) to 17±3% of the control: this depolarizing action was not decreased by 6‐cyano‐7‐nitroquinoxaline‐2,3‐dione (CNQX, 100 μ M ), and only slightly decreased by high concentrations of D ‐2‐amino‐5‐phosphonopentanoic acid ( D ‐AP5, 100 μ M ), suggesting that L ‐F 2 CCG‐I activates mainly metabotropic glutamate receptors.L ‐F 2 CCG‐I preferentially depressed the monosynaptic component of the spinal reflex approximately 3 times more effectively than (2 S ,1′ S ,2′ S )‐2‐(carboxycyclopropyl)glycine ( L ‐CCG‐I). The depressant action of L ‐F 2 CCG‐I (0.2 μ M –0.7 μ M ) on monosynaptic excitation was antagonized by (2 S ,1′ S ,2′ S )‐2‐methyl‐2‐(carboxycyclopropyl)glycine (MCCG, 0.3 m M –1 m M ) and ( S )‐2‐amino‐2‐methyl‐4‐phosphonobutanoic acid (MAP4, 0.3 m M ).DL ‐α‐Aminopimelate (10 and 100 μ M ) selectively potentiated the depression of monosynaptic excitation caused by L ‐CCG‐I (0.2 μ M ) and L ‐F 2 CCG‐I (0.1 μ M ). The actions of (2 S ,1′ R ,2′ R ,3≈prime; R )‐2‐(2,3‐dicarboxycyclopropyl)glycine (DCG‐IV) (50 n M –0.2 μ M ), L ‐2‐amino‐4‐phosphonobutanoic acid ( L ‐AP4) (0.3–1 μ M ), (1 S ,3 R )‐1‐aminocyclopentane‐1,3‐dicarboxylic acid ((1 S ,3 R )‐ACPD) (1–7 μ M ) and baclofen (0.1–0.7 μ M ) were unaffected by DL ‐α‐aminopimelate. The threshold concentration for the potentiating actions of DL ‐α‐aminopimelate was 3 μ M . The depolarization induced by quisqualate (3 μ M , 10 s application) was increased to 115±2% and 137±5% of the control values during combined application of quisqualate with either 30 μ M or 100 μ M DL ‐α‐aminopimelate, respectively. Following the application and subsequent washout of L ‐F 2 CCG‐I, DL ‐α‐aminopimelate (3–100 μ M ) decreased the amplitude of the monosynaptic component of spinal reflexes in a concentration‐dependent manner, indicating a ‘priming’ effect of L ‐F 2 CCG‐I.British Journal of Pharmacology (1998) 123 , 771–779; doi: 10.1038/sj.bjp.0701670