Differential actions of 3-(4-chlorophenyl) glutamic acid stereoisomers and L-trans-pyrrolidine-2,4-dicarboxylic acid upon L-homocysteic acid- and L-glutamic acid-induced responses from rat spinal motoneurones.
The four recently synthesized stereoisomers of 3-(4-chlorophenyl) glutamic acid (chlorpheg) were individually examined for their abilities to potentiate depolarizations of neonatal rat motoneurones evoked by L-homocysteic acid (L-HCA, 10 microM). This property had previously been observed using the racemate and is believed to be mediated by uptake inhibition. Both the (2S,3S)- and (2S,3R)- isomers were selective potentiators of L-HCA- (vs L-Glu) induced depolarizations although the (2S,3S)- isomer was more effective. The (2R,3S)- isomer had a slight but significant depressant action which could be attributed to N-methyl-D-aspartate (NMDA) receptor antagonism. Comparison of the potentiating properties of (2S,3S)- and (2S,3R)-chlorpheg with those of L-trans-pyrrolidine-2,4-dicarboxylic acid (tPDC, a L-Glu uptake inhibitor) upon L-HCA- and L-Glu-evoked responses revealed that both chlorpheg isomers (500 microM each) selectively potentiated responses evoked by L-HCA (10 microM) but had no significant effect upon those evoked by L-Glu (50 microM). On the other hand, use of tPDC at the same concentration significantly enhanced the depolarizations evoked by both amino acids, although its action on L-Glu-evoked responses was greater. It is concluded that (i) the (2S,3S)- isomer and to a lesser extent, the (2S,3R)- isomer of chlorpheg are responsible for the potentiating actions seen with the chlorpheg racemate used in previous studies and (ii) (2R,3S)-chlorpheg is a weak NMDA antagonist. The apparently selective action of (2S,3S)- and (2S,3R)-chlorpheg upon L-HCA-relative to L-Glu-induced depolarizations supports the existence of multiple excitatory amino acid uptake sites, some of which may yet be unidentified.
Chalmers
D J
DJ
Department of Pharmacology, School of Medical Sciences, Bristol, U.K.
Jane
D E
DE
Sunter
D C
DC
Thompson
G A
GA
Udvarhelyi
P M
PM
Kilpatrick
I C
IC
Watkins
J C
JC
D000818:Animals; D003998:Dicarboxylic Acids / Q000494:pharmacology*; D004347:Drug Interactions; D005971:Glutamates / Q000494:pharmacology*; D018698:Glutamic Acid; D006710:Homocysteine / Q000031:analogs & derivatives; D066298:In Vitro Techniques; D008564:Membrane Potentials / Q000187:drug effects; D009046:Motor Neurons / Q000187:drug effects*; D011759:Pyrrolidines / Q000494:pharmacology*; D051381:Rats; D013116:Spinal Cord / Q000187:drug effects*; D013237:Stereoisomerism
D003998:Dicarboxylic Acids; D005971:Glutamates; D011759:Pyrrolidines; D006710:Homocysteine; C007956:homocysteic acid; D018698:Glutamic Acid; C045418:3-(4-chlorophenyl)glutamic acid; C083486:pyrrolidine-2,4-dicarboxylic acid