New phenylglycine derivatives with potent and selective antagonist activity at presynaptic glutamate receptors in neonatal rat spinal cord.

D E Jane, K Pittaway, D C Sunter, N K Thomas, J C Watkins

Index: Neuropharmacology 34 , 851-856, (1995)

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Abstract

The depression of the monosynaptic excitation of neonatal rat motoneurones produced by the metabotropic glutamate receptor (mGluR) agonists (1S,3S)-1-aminocyclopentane-1, 3-dicarboxylate (ACPD) or L-2-amino-4-phosphonobutyrate (L-AP4) was antagonized by three novel phenylglycine analogues: (RS)-alpha-methyl-4-sulphonophenylglycine (MSPG), (RS)-alpha-methyl-4-phosphonophenylglycine (MPPG) and (RS)-alpha-methyl-4-tetrazolylphenylglycine (MTPG). The potencies of all the new compounds were greater than that of the previously reported (RS)-alpha-methyl-4-carboxyphenylglycine (MCPG). For L-AP4-sensitive presynaptic mGluRs, the order of antagonist potency found was MPPG > MSPG > MTPG > MCPG. In contrast, the order of antagonist potency found for (1S,3S)-ACPD-sensitive presynaptic mGluRs was MTPG > MPPG > MSPG > MCPG. To date, MPPG (KD 9.2 microM) is the most potent L-AP4-sensitive receptor antagonist yet tested on the neonatal rat spinal cord. In addition, MTPG (KD 77 microM) is the most potent antagonist yet tested for (1S,3S)-ACPD-sensitive receptors in this preparation.