Potentiation by DL‐α‐aminopimelate of the inhibitory action of a novel mGluR agonist (L‐F₂CCG‐I) on monosynaptic excitation in the rat spinal cord

Abstract

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. (2S,1′S,2′S)‐ and (2S,1′R,2′S)‐2‐(2‐carboxy‐3,3‐difluorocyclopropyl)glycine (L‐F2CCG‐I and L‐F2CCG‐IV) were the most potent in causing depolarization, their threshold concentrations being approximately 1 μM. The depolarization evoked by L‐F2CCG‐I (30 μM) was depressed by (+)‐α‐methyl‐4‐carboxyphenylglycine (MCPG, 1 mM (n=4)) to 17±3% of the control: this depolarizing action was not decreased by 6‐cyano‐7‐nitroquinoxaline‐2,3‐dione (CNQX, 100 μM), and only slightly decreased by high concentrations of D‐2‐amino‐5‐phosphonopentanoic acid (D‐AP5, 100 μM), suggesting that L‐F2CCG‐I activates mainly metabotropic glutamate receptors. L‐F2CCG‐I preferentially depressed the monosynaptic component of the spinal reflex approximately 3 times more effectively than (2S,1′S,2′S)‐2‐(carboxycyclopropyl)glycine (L‐CCG‐I). The depressant action of L‐F2CCG‐I (0.2 μM–0.7 μM) on monosynaptic excitation was antagonized by (2S,1′S,2′S)‐2‐methyl‐2‐(carboxycyclopropyl)glycine (MCCG, 0.3 mM–1 mM) and (S)‐2‐amino‐2‐methyl‐4‐phosphonobutanoic acid (MAP4, 0.3 mM). DL‐α‐Aminopimelate (10 and 100 μM) selectively potentiated the depression of monosynaptic excitation caused by L‐CCG‐I (0.2 μM) and L‐F2CCG‐I (0.1 μM). The actions of (2S,1′R,2′R,3≈prime;R)‐2‐(2,3‐dicarboxycyclopropyl)glycine (DCG‐IV) (50 nM–0.2 μM), L‐2‐amino‐4‐phosphonobutanoic acid (L‐AP4) (0.3–1 μM), (1S,3R)‐1‐aminocyclopentane‐1,3‐dicarboxylic acid ((1S,3R)‐ACPD) (1–7 μM) and baclofen (0.1–0.7 μM) were unaffected by DL‐α‐aminopimelate. The threshold concentration for the potentiating actions of DL‐α‐aminopimelate was 3 μM. The depolarization induced by quisqualate (3 μM, 10 s application) was increased to 115±2% and 137±5% of the control values during combined application of quisqualate with either 30 μM or 100 μM DL‐α‐aminopimelate, respectively. Following the application and subsequent washout of L‐F2CCG‐I, DL‐α‐aminopimelate (3–100 μM) decreased the amplitude of the monosynaptic component of spinal reflexes in a concentration‐dependent manner, indicating a ‘priming’ effect of L‐F2CCG‐I. British Journal of Pharmacology (1998) 123, 771–779; doi:

Natural Occurrence, Syntheses, and Applications of Cyclopropyl-Group-Containing α-Amino Acids. 2. 3,4- and 4,5-Methanoamino Acids

“…It is noteworthy that the potency of l -F 2 CCG-I to activate group II metabotropic glutamine receptors is about three times higher than that of l -CCG-I. The most distinctive pharmacological change achieved by the introduction of two fluorines was that l -F 2 CCG-III did not exhibit the inhibitory action of l -CCG-III upon Na + -dependent glutamate uptake. , …”

“…The most distinctive pharmacological change achieved by the introduction of two fluorines was that L-F 2 CCG-III did not exhibit the inhibitory action of L-CCG-III upon Na + -dependent glutamate uptake. 152,153 2. 239) (Scheme 42, only the conversion of the aldehyde (()-237a to PCCG-1 through -4 is depicted, whereas the identical transformations of (()-237b to PCCG-5 through -8, (()-237c to PCCG-9 through -12, and (()-237d to PCCG-13 through -16 are not shown).…”

Metabotropic Glutamate Receptors as Drug Targets

“…L-CCG-I Non specific [447,448] GII and GIII (GII>GI>GIII) L-3'-F2CCG-I Non specific [449] GII and GIII ACPT II Non selective mGluR1 KB~100 [475] GII and GIII mGluR2~mGluR4…”

Conformationally Constrained Analogues ofL-Glutamate as Subtype-Selective Modulators of Metabotropic Glutamate Receptors

“…The potency of trans-MCG-I was 2 times that of cis-MCG-I and almost the same as that of L-CCG-I (26,27). Replacement of the two protons at the 3Ј-position with two fluorine atoms led to (2S,1ЈS,2ЈS)-2-(2-carboxy)-3,3-difluorocyclopropyl)glycine (L-F 2 CCG-I), which was found to preferentially depress the monosynaptic component of the spinal reflex approximately 3 times more effectively than L-CCG-I (28). However, if a bulky group such as a phenyl group was introduced at the 3Ј-position cis to the 2Ј-carboxylic group, the resultant…”