Characterization of the L-2-amino-4-phosphonobutanoic acid (L-AP4) receptor using conformationally constrained analogues of AP4

scL-Glutamic acid, scL-aspartic acid, and/or structurally related compounds are thought to be the major excitatory neurotransmitters in the central nervous system (CNS).{dollar}sp{lcub}1-3{rcub}{dollar} These compounds are collectively known as excitatory amino acids (EAAs). Currently, there are four proposed EAA receptors. These receptors are differentiated pharmacologically by their rank potencies to specific agonists and antagonists.; One of these EAA receptor subtypes, the scL-2-amino-4-phosphonobutanoic acid (scL-AP4) receptor, is delineated by the inhibition of evoked responses by micromolar concentration of scL-AP4. While application of millimolar concentrations of scL-AP4 will depolarize most neurons in the CNS, only a limited number of systems are sensitive to micromolar concentrations of scL-AP4. Until recently, the pharmacological tools necessary for the characterization of scL-AP4 receptors in these scL-AP4-sensitive systems were not available.; This thesis describes the actions of three newly synthesized cyclic AP4 analogues and their use to characterize scL-AP4 receptors. Two cyclopropyl AP4 analogues, (E)- and (Z)-2,3-methano-4-phosphonobutanoic acid, and the cyclobutylene AP4 analogue 1-amino-3-(phosphonomethylene)-cyclobutane-1-carboxylic acid were synthesized by Heather B. Kroona in the laboratory of Dr. Rodney L. Johnson (Dept. of Medicinal Chemistry, U. of MN) and tested for biological activity at scL-AP4 receptors. Modeling studies indicate that the biologically active conformations of the cyclopropyl AP4 analogues, and therefore scL-AP4 itself, are in an extended form. The relatively high potency of the rigid cyclobutylene AP4 analogue confirmed this hypothesis.; In addition to modeling studies, the conformationally constrained analogues proved useful pharmacological tools for studying the scL-AP4 receptors of four scL-AP4-sensitive systems. The rank-order potencies of four different systems which are sensitive to scL-AP4 were determined: two retinal (mudpuppy, rabbit) and two hippocampal slice (rat lateral perforant path; guinea pig mossy fiber-CA3) preparations. In addition, the pharmacology of four non- scL-AP4 sensitive systems in the hippocampus was examined. Retinal experiments were performed by Wallace B. Thoreson in the laboratory of Robert F. Miller (Dept. Physiology, U. of MN). The results of these experiments are consistent with the possibility that the scL-AP4 receptors comprise a family of receptor proteins.