title: Potent antagonists at the L-AP4- and (1S,3S)-ACPD-sensitive presynaptic metabotropic glutamate receptors in the neonatal rat spinal cord.
abstract: In this report we describe the actions of two novel compounds, (RS)-alpha-cyclopropyl-4-phosphonophenylglycine (CPPG) and (S)-alpha-ethylglutamate (EGLU), which are potent antagonists at two types of presynaptic metabotropic glutamate (mGlu) receptors in the neonatal rat spinal cord. Selective activation of these receptors by L-2-amino-4-phosphonobutyrate (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 produces rightward parallel shifts of the dose-response curves for both L-AP4- and (1S,3S)-ACPD, with Schild slope in each case close to unity, consistent with a competitive mechanism of antagonism. CPPG is the most potent antagonist yet described for both L-AP4- and (1S,3S)-ACPD-sensitive presynaptic mGlu receptors but displays a 30-fold selectivity for the L-AP4-sensitive receptor over the (1S,3S)-ACPD-sensitive receptor (KD values 1.7 microM and 53 microM, respectively). EGLU, on the other hand, is selective for the (1S,3S)-ACPD-sensitive receptor, displaying little or no activity at the L-AP4-sensitive site. EGLU produces a rightward parallel shift of the dose-response curve to (1S,3S)-ACPD, with Schild slope close to unity, again indicative of a competitive mode of antagonism (KD 66 microM). Both CPPG and EGLU displayed only weak or no antagonist activity at postsynaptic metabotropic and ionotropic glutamate receptors.
authors.affiliation: Department of Pharmacology, School of Medical Sciences, Bristol, U.K.
authors.forename: D E
authors.initials: DE
authors.lastname: Jane
authors.forename: N K
authors.initials: NK
authors.lastname: Thomas
authors.forename: H W
authors.initials: HW
authors.lastname: Tse
authors.forename: J C
authors.initials: JC
authors.lastname: Watkins
mesh_terms: D000613:Aminobutyrates / Q000494:pharmacology*; D000818:Animals; D000831:Animals, Newborn; D003515:Cycloleucine / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology*; D005971:Glutamates / Q000138:chemical synthesis / Q000494:pharmacology*; D005998:Glycine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D016202:N-Methylaspartate / Q000494:pharmacology; D051381:Rats; D018094:Receptors, Metabotropic Glutamate / Q000819:agonists / Q000037:antagonists & inhibitors*; D017661:Receptors, Presynaptic / Q000819:agonists / Q000037:antagonists & inhibitors*; D013116:Spinal Cord / Q000378:metabolism*; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid / Q000494:pharmacology
chemical_list: D000613:Aminobutyrates; D018690:Excitatory Amino Acid Agonists; D005971:Glutamates; D018094:Receptors, Metabotropic Glutamate; D017661:Receptors, Presynaptic; C104331:cyclopropyl-4-phosphonophenylglycine; D003515:Cycloleucine; C017302:alpha-ethylglutamic acid; C036361:1-amino-1,3-dicarboxycyclopentane; D016202:N-Methylaspartate; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; C012729:2-amino-4-phosphonobutyric acid; D005998:Glycine