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

  • Br J Pharmacol. 2003 Aug;139(8):1523-31. doi: 10.1038/sj.bjp.0705377.
Jacqueline C Miller  1 ,  Patrick A Howson ,  Stuart J Conway ,  Richard V Williams ,  Barry P Clark ,  David E Jane
Affiliations
  • 1. Department of Pharmacology, School of Medical Sciences, Bristol BS8 1TD. Eli Lilly and Co., Erl Wood Manor, Windlesham, Surrey GU20 6PH.
PMID: 12922940 DOI: 10.1038/sj.bjp.0705377
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 micro M (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 micro M). 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.

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