Phenylglycine derivatives as antagonists of group III metabotropic glutamate receptors expressed on neonatal rat primary afferent terminals
British Journal of Pharmacology (2003) 139, 1523–1531
& 2003 Nature Publishing Group All rights reserved 0007 – 1188/03 $25.00 www.nature.com/bjp Phenylglycine derivatives as antagonists of group III metabotropic glutamate receptors expressed on neonatal rat primary afferent terminals 1
Jacqueline C. Miller, 1Patrick A. Howson, 1Stuart J. Conway, 1Richard V. Williams,
Barry P. Clark & *,1David E. Jane
2
1
Department of Pharmacology, School of Medical Sciences, Bristol BS8 1TD and 2Eli Lilly and Co., Erl Wood Manor,
Windlesham, Surrey GU20 6PH
Keywords:
Abbreviations:
1 Three novel phenylglycine analogues; (RS)-a-methyl-3-chloro-4-phosphonophenylglycine
(UBP1110), (RS)-a-methyl-3-methoxy-4-phosphonophenylglycine (UBP1111) and (RS)-a-methyl-3methyl-4-phosphonophenylglycine (UBP1112) antagonised the depression of the fast component of the dorsal root-evoked ventral root potential induced by (S)-AP4 with apparent KD values of:
7.472.3, 5.470.6 and 5.170.3 mm (all n ¼ 3), respectively.
2 A Schild analysis of the antagonism of (S)-AP4 induced depression of synaptic transmission by
UBP1112 revealed a pA2 value of 5.3 and a slope of 0.8170.26 (n ¼ 9).
3 None of the phenylglycines tested were potent antagonists of responses mediated by group II mGlu receptors (apparent KD values 4480 mm). 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.
British Journal of Pharmacology (2003) 139, 1523–1531. doi:10.1038/sj.bjp.0705377
Neonatal rat spinal cord; phenylglycine; mGlu receptors; antagonist; mGlu8; UBP1110; UBP1111; UBP1112
(1S,3S)-ACPD, (1S,3S)-1-aminocyclopentane-1,3-dicarboxylic acid;
& 2003 Nature Publishing Group All rights reserved 0007 – 1188/03 $25.00 www.nature.com/bjp Phenylglycine derivatives as antagonists of group III metabotropic glutamate receptors expressed on neonatal rat primary afferent terminals 1
Jacqueline C. Miller, 1Patrick A. Howson, 1Stuart J. Conway, 1Richard V. Williams,
Barry P. Clark & *,1David E. Jane
2
1
Department of Pharmacology, School of Medical Sciences, Bristol BS8 1TD and 2Eli Lilly and Co., Erl Wood Manor,
Windlesham, Surrey GU20 6PH
Keywords:
Abbreviations:
1 Three novel phenylglycine analogues; (RS)-a-methyl-3-chloro-4-phosphonophenylglycine
(UBP1110), (RS)-a-methyl-3-methoxy-4-phosphonophenylglycine (UBP1111) and (RS)-a-methyl-3methyl-4-phosphonophenylglycine (UBP1112) antagonised the depression of the fast component of the dorsal root-evoked ventral root potential induced by (S)-AP4 with apparent KD values of:
7.472.3, 5.470.6 and 5.170.3 mm (all n ¼ 3), respectively.
2 A Schild analysis of the antagonism of (S)-AP4 induced depression of synaptic transmission by
UBP1112 revealed a pA2 value of 5.3 and a slope of 0.8170.26 (n ¼ 9).
3 None of the phenylglycines tested were potent antagonists of responses mediated by group II mGlu receptors (apparent KD values 4480 mm). 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.
British Journal of Pharmacology (2003) 139, 1523–1531. doi:10.1038/sj.bjp.0705377
Neonatal rat spinal cord; phenylglycine; mGlu receptors; antagonist; mGlu8; UBP1110; UBP1111; UBP1112
(1S,3S)-ACPD, (1S,3S)-1-aminocyclopentane-1,3-dicarboxylic acid;
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