A conformationally constrained competitive inhibitor of the sodium-dependent glutamate transporter in forebrain synaptosomes: L-anti-endo-3,4-methanopyrrolidine dicarboxylate.
A series of L-3,4-methanopyrrolidine dicarboxylate isomers were investigated as potential inhibitors of the high affinity, sodium-dependent glutamate transporter in rat forebrain synaptosomes. Of the isomers tested, only L-anti-endo-3,4-methanopyrrolidine dicarboxylate (L-anti-endo-MPDC) blocked the uptake of [3H]D-aspartate, a non-metabolized substrate. Kinetic analysis demonstrated that L-anti-endo-MPDC is a potent competitive inhibitor (Ki = 5 microM) comparable to that of L-glutamate and L-trans-2,4-pyrrolidine dicarboxylate (L-trans-2,4-PDC). Conformational analysis of L-glutamate, L-trans-2,4-PDC and L-anti-endo-MPDC are used to refine the pharmacophore model of the transporter binding site.
Department of Pharmaceutical Sciences, University of Montana, Missoula 59812.
R J
RJ
Bridges
F E
FE
Lovering
H
H
Koch
C W
CW
Cotman
A R
AR
Chamberlin
D027322:Amino Acid Transport System X-AG; D000818:Animals; D001224:Aspartic Acid / Q000378:metabolism; D001665:Binding Sites; D001692:Biological Transport / Q000502:physiology; D003998:Dicarboxylic Acids / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D006023:Glycoproteins / Q000037:antagonists & inhibitors*; D066298:In Vitro Techniques; D007700:Kinetics; D008297:Male; D008968:Molecular Conformation; D016548:Prosencephalon / Q000378:metabolism* / Q000648:ultrastructure; D011485:Protein Binding; D011759:Pyrrolidines / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012964:Sodium / Q000502:physiology*; D013574:Synaptosomes / Q000378:metabolism*
C090670:3,4-methanopyrrolidine dicarboxylate; D027322:Amino Acid Transport System X-AG; D003998:Dicarboxylic Acids; D006023:Glycoproteins; D011759:Pyrrolidines; D001224:Aspartic Acid; D012964:Sodium