Conformationally defined neurotransmitter analogues. Selective inhibition of glutamate uptake by one pyrrolidine-2,4-dicarboxylate diastereomer.
In order to determine the conformational requirements for binding of L-glutamate to the proteins involved in the process of neurotransmission, rigid analogues containing an embedded glutamate moiety have been prepared. These "conformer mimics", the pyrrolidine-2,4-dicarboxylates 4, 7, 11, and 14, were synthesized from commercially available trans-4-hydroxy-L-proline and cis-4-hydroxy-D-proline, and then were tested for their ability to inhibit the high-affinity transport of [3H]-L-glutamate into synaptosomes and to block the binding of radioligands to the NMDA (N-methyl-D-aspartate), KA (kainate), and QA (quisqualate) glutamate neurotransmitter receptor sites. While none of the four analogues binds effectively to the excitatory receptors, the L-trans-isomer 7 is a potent and selective competitive inhibitor of L-glutamate transport. These results delineate a specific structural/conformational preference for binding to the uptake system that is distinct from that required for binding to the NMDA, KA, and QA receptors.
Bridges
R J
RJ
Department of Neurology, University of California, Irvine 92717.
Stanley
M S
MS
Anderson
M W
MW
Cotman
C W
CW
Chamberlin
A R
AR
D000818:Animals; D001667:Binding, Competitive; D055598:Chemical Phenomena; D002621:Chemistry; D005971:Glutamates / Q000493:pharmacokinetics*; D018698:Glutamic Acid; D008297:Male; D008968:Molecular Conformation; D018377:Neurotransmitter Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D011759:Pyrrolidines / Q000138:chemical synthesis* / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D017981:Receptors, Neurotransmitter / Q000187:drug effects / Q000378:metabolism; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013574:Synaptosomes / Q000187:drug effects / Q000378:metabolism
D005971:Glutamates; D018377:Neurotransmitter Agents; D011759:Pyrrolidines; D017981:Receptors, Neurotransmitter; D018698:Glutamic Acid