POTENT ANTAGONISTS AT THE L-AP4-SENSITIVE AND (1S,3S)-ACPD-SENSITIVE PRESYNAPTIC METABOTROPIC GLUTAMATE RECEPTORS IN THE NEONATAL RAT SPINAL-CORD

In this report we describe the actions of two novel compounds, (RS)-al pha-cyclopropyl-4-phosphonophenylglycine (CPPG) and (S)-alpha-ethylglu tamate (EGLU), which are potent antagonists at two types of presynapti c metabotropic glutamate (mGlu) receptors in the neonatal rat spinal c ord. Selective activation of these receptors by L-2-amino-4-phosphonob utyrate (L-AP4) or (1S,3S)-1-aminocyclopentane-1,3-dicarboxylic acid ( (1S,3S)-ACPD) results in the depression of the monosynaptic component of the dorsal root-evoked ventral root potential (DR-VRP). CPPG produc es rightward parallel shifts of the dose-response curves for both L-AP 4- and (1S,3S)-ACPD, with Schild slope in each case close to unity, co nsistent with a competitive mechanism of antagonism. CPPG is the most potent antagonist yet described for both L-AP4- and (1S,3S)-ACPD-sensi tive presynaptic mGlu receptors but displays a 30-fold selectivity for the L-AP4-sensitive receptor over the (1S,3S)-ACPD-sensitive receptor (K-D values 1.7 mu M and 53 mu M, respectively). EGLU, on the other h and, is selective for the (1S,3S)-ACPD-sensitive receptor, displaying little or no activity at the L-AP4-sensitive site. EGLU produces a rig htward parallel shift of the dose-response curve to (1S,3S)-ACPD, with Schild slope close to unity, again indicative of a competitive mode o f antagonism (K-D 66 mu M). Both CPPG and EGLU displayed only weak or no antagonist activity at postsynaptic metabotropic and ionotropic glu tamate receptors. Copyright (C) 1996 Elsevier Science Ltd.