Phenylglycine derivatives as antagonists of group III metabotropic glutamate receptors expressed on neonatal rat primary afferent terminals.
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.
Miller
Jacqueline C
JC
Department of Pharmacology, School of Medical Sciences, Bristol BS8 1TD. Eli Lilly and Co., Erl Wood Manor, Windlesham, Surrey GU20 6PH.
Howson
Patrick A
PA
Conway
Stuart J
SJ
Williams
Richard V
RV
Clark
Barry P
BP
Jane
David E
DE
D000818:Animals; D004305:Dose-Response Relationship, Drug; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D005260:Female; D005998:Glycine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology*; D066298:In Vitro Techniques; D008297:Male; D015394:Molecular Structure; D051381:Rats; D017208:Rats, Wistar; D018094:Receptors, Metabotropic Glutamate / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D013126:Spinal Nerve Roots / Q000187:drug effects / Q000378:metabolism*; D013329:Structure-Activity Relationship
D018691:Excitatory Amino Acid Antagonists; D018094:Receptors, Metabotropic Glutamate; C102718:metabotropic glutamate receptor 3; D005998:Glycine