Phenylglycine derivatives as antagonists of group III metabotropic glutamate receptors expressed on neonatal rat primary afferent terminals

JC Miller, PA Howson, Stuart John Conway, RV Williams, BP Clark, DE Jane

Research output: Contribution to journalArticlepeer-review

12 Citations (Scopus)

Abstract

1 Three novel phenylglycine analogues; (RS)-alpha-methyl-3-chloro-4-phosphonophenylglycine (UBP1110), (RS)-alpha-methyl-3-methoxy-4-phosphonophenylglycine (UBP1111) and (RS)-alpha-methyl-3-methyl-4-phosphonophenylglycine (UBP1112) antagonised the depression of the fast component of the dorsal root-evoked ventral root potential induced by (S)-AP4 with apparent K-D values of: 7.4 +/- 2.3, 5.4 +/- 0.6 and 5.1 +/- 0.3 muM (all n = 3), respectively.

2 A Schild analysis of the antagonism of (S)-AP4 induced depression of synaptic transmission by UBP1112 revealed a pA(2) value of 5.3 and a slope of 0.81 +/- 0.26 (n = 9).

3 None of the phenylglycines tested were potent antagonists of responses mediated by group II mGlu receptors (apparent K-D values >480 muM). UBP1112 when tested at a concentration of 1 mM had little or no activity on (S)-3,5-DHPG-, NMDA-, AMPA- or kainate-induced responses on motoneurones.

4 UBP1110, UBP1111 and UBP1112 are at least 100-fold selective for group III over group I and II mGlu receptors expressed in the spinal cord making them the most potent, selective, antagonists yet tested at (S)-AP4 sensitive receptors in the spinal cord.

Original languageEnglish
Pages (from-to)1523-1531
Number of pages9
JournalBritish Journal of Pharmacology
Volume139
DOIs
Publication statusPublished - Aug 2003

Keywords

  • neonatal rat spinal cord
  • phenylglycine
  • mGlu receptors
  • antagonist
  • mGlu8
  • UBP1110
  • UBP1111
  • UBP1112
  • SPINAL-CORD
  • ANTICONVULSANT ACTIVITY
  • AGONIST
  • POTENT
  • RESPONSES
  • SUBTYPES
  • (R,S)-4-PHOSPHONOPHENYLGLYCINE
  • SELECTIVITY

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